A Remote Monitoring System to Optimize the Home Management of Oral Anticancer Therapies (ONCO-TreC): Prospective Training-Validation Trial.

BACKGROUND: A platform designed to support the home management of oral anticancer treatments and provide a secure web-based patient-health care professional communication modality, ONCO-TreC, was tested in 3 cancer centers in Italy. OBJECTIVE: The overall aims of the trial are to customize the platform; assess the system's ability to facilitate the shared management of oral anticancer therapies by patients and health professionals; and evaluate system usability and acceptability by patients, caregivers, and health care professionals. METHODS: Patients aged ≥18 years who were candidates for oral anticancer treatment as monotherapy with an Eastern Cooperative Oncology Group performance status score of 0 to 1 and a sufficient level of familiarity with mobile devices were eligible. ONCO-TreC consisted of a mobile app for patients and a web-based dashboard for health care professionals. Adherence to treatment (pill count) and toxicities reported by patients through the app were compared with those reported by physicians in medical records. Usability and acceptability were evaluated using questionnaires. RESULTS: A total of 40 patients were enrolled, 38 (95%) of whom were evaluable for adherence to treatment. The ability of the system to measure adherence to treatment was high, with a concordance of 97.3% (95% CI 86.1%-99.9%) between the investigator and system pill count. Only 60% (3/5) of grade 3, 54% (13/24) of grade 2, and 19% (7/36) of grade 1 adverse events reported by physicians in the case report forms were also reported in the app directly by patients. In total, 94% (33/35) of patients had ≥1 app launch each week, and the median number of daily accesses per patient was 2. Approximately 71% (27/38) and 68% (26/38) of patients used the app for messages and vital sign entering, respectively, at least once during the study period. CONCLUSIONS: ONCO-TreC is an important tool for measuring and monitoring adherence to oral anticancer drugs. System usability and acceptability were very high, whereas its reliability in registering toxicity could be improved. TRIAL REGISTRATION: ClinicalTrials.gov NCT02921724; https://www.clinicaltrials.gov/ct2/show/NCT02921724.

Hydrochar and hydrochar co-compost from OFMSW digestate for soil application: 2. agro-environmental properties.

The work concerns the study of the hydrochar from digestate and hydrochar co-compost characterization as amendments. The processes for hydrochar and co-compost production were described in Part 1 of this work (Scrinzi et al., 2022). The amendment properties of hydrochar (produced at 180-200-220 °C for 3 h) and co-composts (25%, 50%, and 75% hydrochar percentage of digestate substitution) were assessed by phytotoxicity, plant growth bioassay, and soil effect. Different seeds species (Lepidium sativum, Cucumis sativus, and Sorghum bicolor sp.) were dosed at increased concentrations using both wet raw amendments and their water extracts. The chemical characterization showed phytotoxic compounds content depending on both the initial feedstock (digestate) and the HTC process; at the same time, the analysis highlighted the reduction of these compounds by composting (organic acid, polyphenols, salt concentration). The dose-response was analyzed by the Cedergreen-Streibig-Ritz model and the half-maximal effective concentration (EC50) was calculated based on this equation. The soil properties and GHG emissions measurements (CH4, CO2, N2O, and NH3) highlighted the effect on N dynamics and on soil respiration induced by substrates. The HC200 soil application determined a significant impact on CO2 and N2O emission and NH3 volatilization (10.82 mol CO2/m2; 51.45 mmol N2O/m2; 112 mol NH3/m2) and a significant reduction of total N and TOC (46% of TKN and 49% of TOC). The co-compost (75%) showed specific effects after soil application compared to other samples an increase of available P (48%), a greater content of nitrogen (1626 mg/kg dry basis), and a reduction of organic carbon (17%). Our results demonstrate the good quality of co-compost and at the same time the validity of this post-treatment for addressing many issues related to hydrochar use in the soil as an amendment, confirming the suitability of HTC process integration for digestate treatment in anaerobic digestion plants.

Phase II Study of Dehydroepiandrosterone in Androgen Receptor-Positive Metastatic Breast Cancer.

LESSONS LEARNED: The androgen receptor (AR) is present in most breast cancers (BC), but its exploitation as a therapeutic target has been limited.This study explored the activity of dehydroepiandrosterone (DHEA), a precursor being transformed into androgens within BC cells, in combination with an aromatase inhibitor (to block DHEA conversion into estrogens), in a two-stage phase II study in patients with AR-positive/estrogen receptor-positive/human epidermal growth receptor 2-negative metastatic BC.Although well tolerated, only 1 of 12 patients obtained a prolonged clinical benefit, and the study was closed after its first stage for poor activity. BACKGROUND: Androgen receptors (AR) are expressed in most breast cancers, and AR-agonists have some activity in these neoplasms. We investigated the safety and activity of the androgen precursor dehydroepiandrosterone (DHEA) in combination with an aromatase inhibitor (AI) in patients with AR-positive metastatic breast cancer (MBC). METHODS: A two-stage phase II study was conducted in two patient cohorts, one with estrogen receptor (ER)-positive (resistant to AIs) and the other with triple-negative MBC. DHEA 100 mg/day was administered orally. The combination with an AI aimed to prevent the conversion of DHEA into estrogens. The main endpoint was the clinical benefit rate. The triple-negative cohort was closed early. RESULTS: Twelve patients with ER-positive MBC were enrolled. DHEA-related adverse events, reported in four patients, included grade 2 fatigue, erythema, and transaminitis, and grade 1 drowsiness and musculoskeletal pain. Clinical benefit was observed in one patient with ER-positive disease whose tumor had AR gene amplification. There was wide inter- and intra-patient variation in serum levels of DHEA and its metabolites. CONCLUSION: DHEA showed excellent safety but poor activity in MBC. Although dose and patient selection could be improved, high serum level variability may hamper further DHEA development in this setting.

Androgen receptor in advanced breast cancer: is it useful to predict the efficacy of anti-estrogen therapy?

BACKGROUND: Androgen receptor (AR) is widely expressed in breast cancer (BC) but its role in estrogen receptor (ER)-positive tumors is still controversial. The AR/ER ratio has been reported to impact prognosis and response to antiestrogen endocrine therapy (ET). METHODS: We assessed whether AR in primary tumors and/or matched metastases is a predictor of efficacy of first-line ET in advanced BC. Patients who had received first-line ET (2002-2011) were recruited, while those given concomitant chemotherapy or trastuzumab or pretreated with > 2 lines of chemotherapy were excluded. ER, progesterone receptor (PgR), Ki67 and AR expression were assessed by immunohistochemistry, and HER2 mainly by fluorescent in-situ hybridization. Cut-offs of 1 and 10% immunostained cells were used to categorize AR expression. RESULTS: Among 102 evaluable patients, biomarkers were assessed in primary tumors in 70 cases and in metastases in 49, with 17 patients having both determinations. The overall concordance rate between primary tumors and metastases was 64.7% (95% CI 42%-87.4%) for AR status. AR status did not affect TTP significantly, whereas PgR and Ki67 status did. AR/PgR ≥0.96 was associated with a significantly shorter TTP (HR = 1.65, 95% CI 1.05-2.61, p = 0.028). AR status in primary tumors or metastases was not associated with progressive disease (PD) as best response. In contrast, Ki67 ≥ 20% and PgR < 10% showed a statistically significant association with PD as best response. CONCLUSIONS: AR expression does not appear to be useful to predict the efficacy of ET in advanced BC, whereas Ki67 and PgR exert a greater impact on its efficacy.

A phase II study of a dose-density regimen with fluorouracil, epirubicin, and cyclophosphamide on days 1 and 4 every 14 days with filgrastim support followed by weekly paclitaxel in women with primary breast cancer.

BACKGROUND: Recent evidence shows that use of anthracycline and taxane adjuvant chemotherapy and dose-dense regimens, consisting of more frequent administration of the drugs, have improved outcomes for breast cancer patients. In this study, we evaluated administration of an epirubicin-based regimen with paclitaxel in a sequential, dose-dense schedule as adjuvant treatment for patients with high-risk primary breast cancer. METHODS: In a phase II Simon two-stage design study, we evaluated the feasibility of a modified fluorouracil, epirubicin, and cyclophosphamide (FEC) regimen at high dose intensity (fluorouracil 500 mg/m(2) i.v. on days 1 and 4, epirubicin 60 mg/m(2) i.v. on days 1 and 4, and cyclophosphamide 500 mg/m(2) i.v. on days 1 and 4; all drugs were administered every 14 days for 3 cycles) with granulocyte colony-stimulating factor support followed by dose-intense weekly paclitaxel 100 mg/m(2) for 8 cycles. In 11 patients with breast cancer following quadrantectomy (n = 8) or modified radical mastectomy (n = 3), any grade 3 (G3) or higher nonhematologic toxicity (excluding alopecia, nausea or vomiting, and bone pain, which might be a consequence of the administration of filgrastim) and adherence to the scheduled dose-dense treatment (deliverability) were monitored with the purpose of enrolling an additional 27 patients in the case of a satisfying toxicity profile and deliverability of the planned treatment (at least 7 patients completing the treatment). RESULTS: Five of 11 patients experienced G3 or higher nonhematologic toxicity during the FEC regimen. We did not observe G3 or higher nonhematologic toxicity related to paclitaxel treatment. In particular, three patients experienced G3 fatigue, one patient had G3 oral mucositis, three patients had G3 hypokalemia, one patient had G3 syncope, one patient had G3 transaminitis (alanine aminotransferase), one patient experienced G4 pulmonary thromboembolism, and 1 patient had a G3 breast infection. Four of 11 patients received the regimen with a 25% dose reduction of day 1 and 4 administrations of FEC. Seven of 11 patients required FEC delay ≥7 days in at least 1 cycle, regardless of dose intensity. Two patients failed to complete the FEC regimen. Two of the remaining 9 patients were treated with paclitaxel delay ≥7 days in at least one cycle. After a median follow-up of 28 months, 9 patients were continuously disease free. CONCLUSION: The tolerability rate of a dose-density regimen with FEC followed by weekly paclitaxel was considered not promising for completing the accrual of this study.

Efficacy of endocrine therapy in relation to progesterone receptor and Ki67 expression in advanced breast cancer.

We assessed whether progesterone receptor (PgR) and Ki67 in primary tumors and/or matched metastases are predictors of clinical benefit from first-line endocrine therapy (ET) in advanced breast cancer. We evaluated patients treated at our institute with first-line ET (2002-2011), excluding those receiving concomitant chemotherapy or trastuzumab or pretreated with >2 lines of chemotherapy. A cut-off of 20 % immunostained cells was used for PgR and Ki67. The main endpoint was time-to-progression (TTP). Groups were compared by the log-rank test and Cox multivariate analysis. In the 135 assessable patients (93 % were receiving an aromatase inhibitor; biomarker assessment had been performed on primary tumors in 77 cases, on metastases in 23 and on both in 35), median TTP was 16 months (median follow-up 43 months). The overall discordance rate between primary tumors and metastases was 23 % for Ki67 and 31 % for PgR. A longer median TTP (24 vs. 12 months, P = 0.012) was seen for PgR >20 % in metastases. Ki67 showed a trend for TTP prediction in the entire case series (P = 0.062). Patients with high Ki67 and low PgR in metastases had a median TTP of only 5 months. High Ki67 in primary tumors (P = 0.026) or metastases (P = 0.01) predicted disease progression at the first evaluation. PgR in metastases remained a significant independent predictor of TTP at multivariate analysis (HR 2.45). In an ER-high population, PgR >20 % in metastases identified patients with a long TTP on endocrine treatment, while Ki67 >20 % was associated with an increased risk of non-response.

Pure anti-tumor effect of zoledronic acid in naïve bone-only metastatic and locally advanced breast cancer: proof from the "biological window therapy".

The study investigated the anti-tumour effect of zoledronic acid (ZA) administered alone in a biological window therapy in naïve bone-only metastatic and locally advanced breast cancer (LABC) patients. 33 patients with LABC (Group 1) and 20 patients with a first diagnosis of bone metastasis only (Group 2) received 4 mg single dose of ZA, 14 days (biological window) before starting any treatment. In Group 1, Ki67, CD34, p53/bcl-2 and caspase 3 expression along with the adenosine triphosphate (ATP) levels and RNA disruption index were evaluated as markers of tumor growth in tumour specimens obtained before and after ZA administration (basal, day 14). In Group 2, the total enumeration of circulating tumour cells (CTCs), and of M30+ve CTCs along with the soluble marker of cell death (M30/M65) were carried-out as markers of tumor dissemination at baseline, at 48 h and day 14th. In Group 1, there was a significant reduction in Ki67, CD34, bcl-2 expression after 14 days ZA based-treatment (p = 0.0032; p = 0.0001, p < 0.00001 respectively). ZA showed a significant increase of RNA disruption (p < 0.0076). In Group 2, we observed a significant reduction of CTCs number after 48 h (p = 0.0012), followed by a significant rebound at 14 days (p = 0.012). The apoptotic CTCs/M30+ve and M65 levels significantly increased under treatment (p = 0.018 and p = 0.039 respectively) after drug administration when compared to the baseline. These results are the first prospective in vivo data showing the direct pure anti-tumour effect (either on the tumour cell or on CTCs) of ZA.

Long-term vemurafenib therapy in advanced melanoma patients: cutaneous toxicity and prognostic implications.

BACKGROUND: The introduction of targeted therapies for the treatment of BRAF-mutated metastatic melanoma was associated with different cutaneous adverse events (AEs). OBJECTIVES: To describe the type, frequency and severity of cutaneous AEs related to vemurafenib; to understand the association between AEs and vemurafenib efficacy in terms of median overall survival (OS) and median progression-free survival (PFS); to identify molecular characteristics of long-term responders. METHODS: This observational, retrospective, monocentric study included all consecutive patients with unresectable stage III or stage IV melanoma and BRAF V600E mutation that started treatment with vemurafenib between May 2012 and May 2014. RESULTS: 62 patients with a median age of 56 years (range 26-82) were enrolled and received vemurafenib for a median period of 7.9 months (range 0.8-63.7). Among them, 45 patients presented at least one skin AE, 12 reduced the dosage due to cutaneous toxicity, and only one firstly reduced and after stopped the therapy. No specific molecular biomarkers were detected in long-term survivors. CONCLUSIONS: Among long-term survivors, skin AEs seem to be less frequent and less severe. Results on multivariable analysis revealed that the presence of at least one G2 toxicity is a protective factor considering PFS, but not in terms of OS.

Phase II study of liposomal doxorubicin, docetaxel and trastuzumab in combination with metformin as neoadjuvant therapy for HER2-positive breast cancer.

BACKGROUND: The aim of this study was to improve activity over single human epidermal growth factor receptor 2 (HER2)-blockade sequential neaodjuvant regimens for HER2-positive breast cancer, by exploiting the concomitant administration of trastuzumab, taxane and anthracycline, while restraining cardiac toxicity with use of liposomal doxorubicin, and by adding metformin, based on preliminary evidence of antitumor activity. PATIENTS AND METHODS: This multi-center, single-arm, two-stage phase II trial, assessed the safety and the activity of a new treatment regimen for HER2-positive, early or locally advanced breast cancer. Patients received six 21-day cycles of non-pegylated liposomal doxorubicin, 50 mg/m2 intravenously (i.v.) on day 1, docetaxel, 30 mg/m2 i.v. on days 2 and 9, trastuzumab, 2 mg/kg/week i.v. on days 2, 9, and 16 (with 4 mg/kg loading dose), in association with metformin 1000 mg orally twice daily. The primary endpoint was the rate of pathological complete response (pCR) in the breast and axilla (ypT0/is ypN0). A subgroup of patients performed a 3-deoxy-3-18F-fluorothymidine positron emission tomography (FLT-PET) at baseline and after one cycle. RESULTS: Among 47 evaluable patients, there were 18 pCR [38.3%, 95% confidence interval (CI) 24.5-53.6%]. A negative estrogen-receptor status, high Ki67, and histological grade 3 were related with pCR, although only grade reached statistical significance. FLT-PET maximum standardized uptake value after one cycle was inversely related to pCR in the breast (odds ratio 0.29, 95% CI 0.06-1.30, p = 0.11). Toxicity included grade 3-4 neutropenia in 70% and febrile neutropenia in 4% of patients, grade 1-2 nausea/vomiting in 60%/38%, and grade 3 in 4%/2%, respectively, grade 1-2 diarrhea in 72%, and grade 3 in 6%. There were two cases of reversible grade 2 left-ventricular ejection-fraction decrease, and one case of sharp troponin-T increase. CONCLUSIONS: The concomitant administration of trastuzumab, liposomal doxorubicin, docetaxel, and metformin is safe and shows good activity, but does not appear to improve activity over conventional sequential regimens.

How Many Cancer Clinical Trials Can a Clinical Research Coordinator Manage? The Clinical Research Coordinator Workload Assessment Tool.

PURPOSE: Cancer clinical trials (CTs) are now more complex than ever before and require dedicated personnel (clinical research coordinators [CRCs]) to perform regulatory and administrative activities and protocol- and patient-related procedures. We developed a simple tool to measure the workload (WL) of CRCs involved in cancer research and to estimate personnel requirements within a Clinical Trial Center. METHODS: A literature review and 2-month period in which CRCs recorded their activities in a diary provided valuable information that led to the Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori Workload Assessment Tool (IWAT) being divided into three sections: Protocol, On-Treatment Patients, and Follow-Up Patients. Twelve full-time senior CRCs from three sites of the Network measured their monthly WL for 30 months to evaluate IWAT reproducibility and accuracy. RESULTS: The IWAT proved to be a user-friendly tool (3-6 minutes required for each CT), with high reproducibility (interobserver reproducibility ranged from 82% to 100% for each IWAT item). In December 2017, the Network had 185 ongoing CTs, with a median of 2.5 active centers for each CT. On the basis of 448 total IWAT measures by CRCs, the majority of trials were academic (57%) or dealt with advanced disease (77%). The median IWAT WL score for each study was 20.98 ± 22.90 (range, 2-188) and 475 ± 229 (range, 150 [junior staff] - 930 [extreme heavy WL]) for each CRC. On the basis of our experience, a monthly WL score of 500-600 was considered an appropriate value for a full-time CRC. CONCLUSION: The IWAT could prove useful in evaluating CT complexity, estimating appropriate CRC WLs, and defining personnel requirements. Independent validation by other CRCs working in different organizational contexts and in different countries is needed.

Evaluation of Androgen Receptor in Relation to Estrogen Receptor (AR/ER) and Progesterone Receptor (AR/PgR): A New Must in Breast Cancer?

Steroid nuclear receptors are known to be involved in the regulation of epithelial-mesenchymal transition process with important roles in invasion and metastasis initiation. Androgen receptor (AR) has been extensively studied, but its role in relation to breast cancer patient prognosis remains to be clarified. AR/ER ratio has been reported to be an unfavorable prognostic marker in early primary breast cancer, but its role in the patients with advanced disease has to be cleared. We retrospectively analyzed ER, PgR, and AR expression on a case series of 159 specimens of primary BC samples by using immunohistochemistry and 89 patients of these had luminal tumors for which AR and ER expression and survival data were available. For twenty-four patients both primary and metastatic tumors were available. A significantly shorter overall survival was observed in primary tumors with AR/PgR ratio ≥ 1.54 (HR = 2.27; 95% CI 1.30-3.97; p = 0.004). Similarly OS was significantly shorter when ER/PgR ratio ≥2 in primary tumors (HR = 1.89; 95% CI 1.10-3.24; p = 0.021). The analysis of the 24 patients who had biomarker determinations both in primary tumors and metastasis showed a better OS when AR/ER ratio in the metastasis was ≥ 0.90 (p = 0.022). Patients with a high AR/ER ratio in primary tumor that remained high in the metastasis had better prognosis in terms of OS (p = 0.011). Despite we suggested that the ratios AR/ER and AR/PgR could be used to identify patients with different prognosis, their real value needs to be better clarified in different BC settings through prospective studies.

Clinical utility of fulvestrant in the treatment of breast cancer: a report on the emerging clinical evidence.

Fulvestrant is the first selective estrogen receptor (ER) downregulator available in clinical practice. It is a pure antiestrogen with no agonistic effects, leading to degradation of ER alpha, with activity in tamoxifen-resistant breast cancer (BC) models. Pharmacokinetic and pharmacodynamic studies and several postmarketing clinical trials led to the definition of the optimal dose at 500 mg intramuscularly on days 1, 15, and 29 and then every 28 days. Targeting ER alpha, fulvestrant is a cornerstone of treatment in luminal BCs, whose growth is largely driven by the ER pathway. In endocrine therapy-naïve patients with hormone receptor-positive, HER2- advanced BC (ABC), fulvestrant yielded significantly longer progression-free survival compared to anastrozole in the Phase III FALCON study. Due to its mechanism of action and pharmacokinetic properties, fulvestrant is an ideal backbone for combination therapies. Preclinical studies have shown synergism with drugs acting on signaling pathways involved in the development of endocrine resistance, among which the cyclin D/cyclin-dependent kinase 4-6/retinoblastoma pathway and the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin pathway, contributing to overcoming or delaying endocrine resistance. In the Phase III PALOMA-3 trial, a combination of the cyclin-dependent kinase 4/6 inhibitor palbociclib with fulvestrant significantly improved progression-free survival over fulvestrant alone in women with hormone receptor positive, HER2- ABC progressing during prior endocrine therapy. This led to approval of the combination in this clinical setting. Similar results were obtained with abemaciclib and ribociclib. Combination with pan-PI3K inhibitors, though showing some efficacy, was hampered by the toxicity of these agents, and studies in combinations with more selective inhibitors of the α-catalytic subunit of PI3K are ongoing. Fulvestrant has shown partial activity also in patients with tumors harboring mutations of the ESR1 gene. It is thus a key drug in the treatment of ABC, whose role in combination with new targeted agents is still evolving.

Androgen Receptor Expression in Breast Cancer: What Differences Between Primary Tumor and Metastases?

Genomic studies have shown that the androgen receptor (AR) pathway plays an important role in some breast cancer subtypes. However few data are present on the concordance between AR expression in primary tumors and metastases. We investigated AR expression by using immunohistochemistry (IHC) in 164 primary tumors and 83 metastases, to explore its distribution in the different tumor subtypes and its concordance between the two sample types and according to sampling time. AR was more highly expressed in luminal A and B than HER2-positive and triple negative primary tumors. A similar distribution was found in metastases, and the concordance of AR expression between primary tumors and metastases was greater than 60%. No association between sampling time and AR expression was observed. We found a good concordance of AR expression between primary tumor and metastasis, but the variability remains high between the two types of specimens, regardless of the variation in sampling time. For this reason, if used for treatment decisions, AR evaluation should be repeated in each patient whenever a new biopsy is performed, as commonly done for the other breast cancer biomarkers.

Progress with palbociclib in breast cancer: latest evidence and clinical considerations.

Deregulation of the cell cycle is a hallmark of cancer, and research on cell cycle control has allowed identification of potential targets for anticancer treatment. Palbociclib is a selective inhibitor of the cyclin-dependent kinases 4 and 6 (CDK4/6), which are involved, with their coregulatory partners cyclin D, in the G1-S transition. Inhibition of this step halts cell cycle progression in cells in which the involved pathway, including the retinoblastoma protein (Rb) and the E2F family of transcription factors, is functioning, although having been deregulated. Among breast cancers, those with functioning cyclin D-CDK4/6-Rb-E2F are mainly hormone-receptor (HR) positive, with some HER2-positive and rare triple-negative cases. Deregulation results from genetic or otherwise occurring hyperactivation of molecules subtending cell cycle progression, or inactivation of cell cycle inhibitors. Based on results of randomized clinical trials, palbociclib was granted accelerated approval by the US Food and Drug Administration (FDA) for use in combination with letrozole as initial endocrine-based therapy for metastatic disease in postmenopausal women with HR-positive, HER2-negative breast cancer, and was approved for use in combination with fulvestrant in women with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. This review provides an update of the available knowledge on the cell cycle and its regulation, on the alterations in cyclin D-CDK4/6-Rb-E2F axis in breast cancer and their roles in endocrine resistance, on the preclinical activity of CDK4/6 inhibitors in breast cancer, both as monotherapy and as partners of combinatorial synergic treatments, and on the clinical development of palbociclib in breast cancer.

Sorafenib for the treatment of breast cancer.

INTRODUCTION: Breast cancer treatment includes many options depending on the tumor clinicopathological profile, which groups breast cancer into various subtypes. Bevacizumab is currently the only drug capable of targeting angiogenesis in breast cancer. Sorafenib has also been studied in combination with other agents. Areas covered: Pharmacological aspects of sorafenib, including results from preclinical studies on breast cancer cells; findings about clinical efficacy and safety in both single-arm and randomized clinical trials; ongoing trials. Expert opinion: Since sorafenib as a single agent has shown limited efficacy in breast cancer, its combination with other drugs is under investigation. Dose reduction is the main challenge when sorafenib is combined with chemotherapy or endocrine therapy. Although randomized phase-II trials on sorafenib plus chemotherapy versus chemotherapy alone have shown potential benefits in progression-free survival, preliminary results from a phase-III study in combination with capecitabine are negative. The definitive results of this trial and results from other ongoing phase-II trials will determine further developments of sorafenib in breast cancer. Although these additional data could help determine the most appropriate dose, drug combination and patient settings, a confirmation of the preliminary negative results reported in the phase-III trial are likely to discourage further use of sorafenib in breast cancer, given its non-negligible toxicity, lack of predicting markers, and the number of more promising drugs for breast cancer.

Optimisation and validation of a remote monitoring system (Onco-TreC) for home-based management of oral anticancer therapies: an Italian multicentre feasibility study.

INTRODUCTION: Despite the growing number of oral agents available for cancer treatment, their efficacy may be reduced due to the lack of adherence, inappropriate adverse event self-management and arbitrary dose adjustment. The management of anticancer therapies could exponentially benefit from the introduction of mobile health technologies in a highly integrated electronic oncology system. METHODS AND ANALYSIS: We plan to customise and fine-tune an existing monitoring TreC platform used in different chronic diseases in the oncology setting. This project follows a multistep approach with two major purposes: 1. participatory design techniques driven by Health Literacy and Patient Reported Outcomes principles in order to adapt the system to the oncology setting involving patients and healthcare providers; 2. a prospective training-validation, interventional, non-pharmacological, multicentre study on a series of consecutive patients with cancer (20 and 60 patients in the training and validation steps, respectively) in order to assess system capability, usability and acceptability. The novel Onco-TreC 2.0 is expected to contribute to improving the adherence and safety of cancer care, promoting patient empowerment and patient-doctor communication. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Independent Ethics Committees of the participating institutions (CEIIAV protocol Number 2549/2015; reference Number 1315-PU). Informed consent will be obtained from all study participants. Findings will be disseminated through peer-reviewed journals, conferences and event presentations. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT02921724); (Pre-results). Other study ID Number: IRST100.18.

Phase Ib dose-finding trial of lapatinib plus pegylated liposomal doxorubicin in advanced HER2-positive breast cancer.

PURPOSE: Combination of anthracyclines with trastuzumab is hampered by cardiotoxicity. Pegylated liposomal doxorubicin and lapatinib could represent a safer alternative to combination therapy. METHODS: In this phase Ib study with 3 + 3 dose escalation design, patients with HER2-positive advanced breast cancer received pegylated liposomal doxorubicin 30 mg/m2 intravenously on day 1 plus lapatinib 1250 (level 1) or 1500 (level 2) mg/day orally on days 1-21 of each 21-day cycle. The aims were to establish the maximum tolerated dose at first cycle, and the activity and safety of multiple cycles. RESULTS: Nine patients out of 11 enrolled were evaluable: 3 at level 1 and 6 at level 2. No dose-limiting toxicities occurred at dose level 1, while 1 (grade 3 diarrhea) occurred at dose level 2, leading to the expansion of this cohort to 6 patients, with no further dose-limiting toxicities. Main grade 1-2 toxicities at first cycle were leucopenia, diarrhea, elevated transaminases, mucositis. Three patients had grade 3 toxicities at subsequent cycles, including colitis, anorexia, stomatitis plus hand-foot syndrome. One partial response, 5 disease stabilizations, and 3 disease progressions were reported. CONCLUSIONS: Combination of pegylated liposomal doxorubicin and lapatinib is feasible and potentially active in pretreated HER2-positive advanced breast cancer patients. TRIAL REGISTRATION: NCT02131506 (ClinicalTrials.gov identifier).

Androgen receptor signaling pathways as a target for breast cancer treatment.

The androgen receptor (AR) is a ligand-dependent transcription factor, and its effects on breast range from physiological pubertal development and age-related modifications to cancer onset and proliferation. The prevalence of AR in early breast cancer is around 60%, and AR is more frequently expressed in ER-positive than in ER-negative tumors. We offer an overview of AR signaling pathways in different breast cancer subtypes, providing evidence that its oncogenic role is likely to be different in distinct biological and clinical scenarios. In particular, in ER-positive breast cancer, AR signaling often antagonizes the growth stimulatory effect of ER signaling; in triple-negative breast cancer (TNBC), AR seems to drive tumor progression (at least in luminal AR subtype of TNBC with a gene expression profile mimicking luminal subtypes despite being negative to ER and enriched in AR expression); in HER2-positive breast cancer, in the absence of ER expression, AR signaling has a proliferative role. These data represent the rationale for AR-targeting treatment as a potentially new target therapy in breast cancer subset using androgen agonists in some AR-positive/ER-positive tumors, AR antagonists in triple-negative/AR-positive tumors and in combination with anti-HER2 agents or with other signaling pathways inhibitors (including PI3K/MYC/ERK) in HER2-positive/AR-positive tumors. Only the ongoing and future prospective clinical trials will allow us to establish which agents are the best option in every specific condition, keeping in mind that there is evidence of opposite androgens and AR agonist/antagonist drug effects on cell proliferation particularly in AR-positive/ER-positive tumors.

Pharmacokinetics, pharmacodynamics and clinical efficacy of pertuzumab in breast cancer therapy.

INTRODUCTION: Pertuzumab is a recombinant, humanized monoclonal antibody that binds to the dimerization domain of human epidermal growth factor receptor 2 (HER2), inhibiting the heterodimerization of HER2 with other HER receptors. It has shown synergy with trastuzumab in preclinical studies, and has led to a significant prolongation of progression-free and overall survival compared with placebo when added to trastuzumab and docetaxel for the first-line treatment of HER2-positive metastatic breast cancer (BC). AREAS COVERED: The HER family of receptors and their pathways, pertuzumab pharmacodynamics and preclinical activity, results from the main clinical trials, new drug combinations being developed, and predictors of response are discussed. EXPERT OPINION: Pertuzumab represents an important anti-HER2 agent that differs from, but is synergistic with, trastuzumab. It is already a standard of care in the first-line treatment of HER2-positive metastatic BC, and studies are ongoing to define its role in the adjuvant setting. It is now imperative to identify which tumors need dual HER2 targeting and to study the activity of pertuzumab in combination with other HER-targeted agents, including anti-HER1, -HER3 or -HER4, which could also prove useful in HER2-normal cancers. Potential competitors are anti-HER3 antibodies and bi- or tri-specific antibodies. Development in combination with phosphoinositide 3-kinase inhibitors or with anti PD-L1 is warranted.

ADAM10 mediates trastuzumab resistance and is correlated with survival in HER2 positive breast cancer.

Trastuzumab prolongs survival in HER2 positive breast cancer patients. However, resistance remains a challenge. We have previously shown that ADAM17 plays a key role in maintaining HER2 phosphorylation during trastuzumab treatment. Beside ADAM17, ADAM10 is the other well characterized ADAM protease responsible for HER ligand shedding. Therefore, we studied the role of ADAM10 in relation to trastuzumab treatment and resistance in HER2 positive breast cancer. ADAM10 expression was assessed in HER2 positive breast cancer cell lines and xenograft mice treated with trastuzumab. Trastuzumab treatment increased ADAM10 levels in HER2 positive breast cancer cells (p ≤ 0.001 in BT474; p ≤ 0.01 in SKBR3) and in vivo (p ≤ 0.0001) compared to control, correlating with a decrease in PKB phosphorylation. ADAM10 inhibition or knockdown enhanced trastuzumab response in naïve and trastuzumab resistant breast cancer cells. Trastuzumab monotherapy upregulated ADAM10 (p ≤ 0.05); and higher pre-treatment ADAM10 levels correlated with decreased clinical response (p ≤ 0.05) at day 21 in HER2 positive breast cancer patients undergoing a trastuzumab treatment window study. Higher ADAM10 levels correlated with poorer relapse-free survival (p ≤ 0.01) in a cohort of HER2 positive breast cancer patients. Our studies implicate a role of ADAM10 in acquired resistance to trastuzumab and establish ADAM10 as a therapeutic target and a potential biomarker for HER2 positive breast cancer patients.