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Background There is no standard treatment recommended at category 1 level in international guidelines for subsequent therapy after cyclin-dependent kinase 4/6 inhibitor (CDK4/6) based therapy. We aimed to evaluate which subsequent treatment oncologists prefer in patients with disease progression under CDKi. In addition, we aimed to show the effectiveness of systemic treatments after CDKi and whether there is a survival difference between hormonal treatments (monotherapy vs. mTOR-based). Methods A total of 609 patients from 53 centers were included in the study. Progression-free-survivals (PFS) of subsequent treatments (chemotherapy (CT, n:434) or endocrine therapy (ET, n:175)) after CDKi were calculated. Patients were evaluated in three groups as those who received CDKi in first-line (group A, n:202), second-line (group B, n: 153) and ≥ 3rd-line (group C, n: 254). PFS was compared according to the use of ET and CT. In addition, ET was compared as monotherapy versus everolimus-based combination therapy. Results The median duration of CDKi in the ET arms of Group A, B, and C was 17.0, 11.0, and 8.5 months in respectively; it was 9.0, 7.0, and 5.0 months in the CT arm. Median PFS after CDKi was 9.5 (5.0–14.0) months in the ET arm of group A, and 5.3 (3.9–6.8) months in the CT arm (p = 0.073). It was 6.7 (5.8–7.7) months in the ET arm of group B, and 5.7 (4.6–6.7) months in the CT arm (p = 0.311). It was 5.3 (2.5–8.0) months in the ET arm of group C and 4.0 (3.5–4.6) months in the CT arm (p = 0.434). Patients who received ET after CDKi were compared as those who received everolimus-based combination therapy versus those who received monotherapy ET: the median PFS in group A, B, and C was 11.0 vs. 5.9 (p = 0.047), 6.7 vs. 5.0 (p = 0.164), 6.7 vs. 3.9 (p = 0.763) months. Conclusion Physicians preferred CT rather than ET in patients with early progression under CDKi. It has been shown that subsequent ET after CDKi can be as effective as CT. It was also observed that better PFS could be achieved with the subsequent everolimus-based treatments after first-line CDKi compared to monotherapy ET.

The HER2-low breast cancer is a newly recognized entity with the clinical characteristics is yet to be defined. We hypothesized that HER2-low breast cancer could lead to an increased rate of brain metastases in patients with localized breast cancer. We tested this hypothesis in a large cohort of breast cancer patients with long follow-up. We included 2686 adult breast cancer patients followed up in Hacettepe University Cancer Center. Patients with 1 + positive HER2 expression and 2 + HER2 expression with a negative FISH were categorized as HER2-low disease. We evaluated the brain metastasis risk with binary logistic regression analyses and reported odds ratios (OR) with 95% confidence intervals (CI). During a median 95.4 (IQR 72.6–123.1) month follow-up, 184 patients developed brain metastasis (6.9%). The brain metastases were developed in 5.1% of the patients with HER2-negative disease, 8.5% of the patients with HER2-low disease, and 10.1% of the patients with HER2-positive disease. A multivariable binary logistic regression model demonstrated an increased risk of brain metastasis in patients with HER2-low disease (OR: 1.611, 95% CI 1.055–2.460, p = 0.027) and in HER2-positive patients (OR: 1.837, 95% CI 1.308–2.580, p

Hypophysitis is rarely reported in patients receiving pembrolizumab-only immunotherapies. Since the clinical presentation is usually as isolated adrenocorticotrophic hormone (ACTH) deficiency, patients may be misjudged as having clinical symptoms due to cancer or chemotherapy. A 49-year-old male with laryngeal cancer applied to our clinic just after the tenth cycle of his pembrolizumab treatment, with weakness and nausea/vomiting. Serum morning cortisol and ACTH were 0.47 mcg/dl and 10.1 pg/ml, respectively; the remaining anterior pituitary hormone levels were normal. Pituitary MRI revealed mild glandular enlargement and loss of posterior pituitary bright-spot. All symptoms and signs improved with low-dose prednisolone. This is the second reported case of pembolizumab-associated isolated ACTH deficiency having abnormal pituitary MRI findings as we have reviewed all reported cases in the literature.Lay abstract Immune check point inhibitors (ICIs) are used in order to enhance antitumoral immune mechanisms in certain cancers. As a result, immune-related side effects have commonly been reported in patients taking ICIs, one of which is hypophysitis. Pembrolizumab is a type of ICI which has rarely been associated with hypophysitis. Since the clinical presentation of pembrolizumab-associated hypophysitis is usually as isolated adrenocorticotrophic hormone deficiency and related cortisol insufficiency, patients may be misjudged as having clinical symptoms due to cancer or chemotherapy, due to shared symptoms such as fatigue, loss of appetite and nausea. Here we have reported a case with pembrolizumab-associated isolated adrenocorticotrophic hormone deficiency and reviewed all other cases available in the literature to improve our understanding of such patients.

Aim: Blood-based biomarkers like prognostic nutritional index (PNI) are readily available biomarkers for immunotherapy efficacy, although the data are limited. So, we aimed to evaluate the association between PNI and overall survival (OS) in immunotherapy-treated patients. Materials & methods: For this retrospective cohort study, data of 150 immunotherapy-treated advanced cancer patients were evaluated. The association between clinical factors and OS was evaluated with multivariate Cox-regression analyses. Results: After a median follow-up of 8.5 months, 94 patients died. The median OS was 11.07 months. The low PNI (hazard ratio [HR]: 2.065; p = 0.001), high lactate dehydrogenase (HR: 2.515; p = 0.001) and poor Eastern Cooperative Oncology Group (ECOG) status (HR: 2.164; p = 0.009) was associated with poorer OS in multivariate analyses. Conclusion: In our experience, survival with immunotherapy was impaired in patients with lower PNI and higher lactate dehydrogenase levels and poorer ECOG status. WOS:000685162800001 34397271 Q3

OBJECTIVES: To evaluate the ocular surface, meibomian glands and corneal structural changes using in vivo confocal microscopy (IVCM) in patients receiving aromatase inhibitor (AI) therapy due to the breast cancer. METHODS: This prospective observational study included 13 patients undergoing AI therapy. The patients were evaluated before the treatment, at 3- and 6-month timepoints of AI therapy. To examine the ocular surface and tear film, corneal sensitivity (CS) measurement with Cochet–Bonnet Aesthesiometer, tear film break-up time (TBUT), lissamine green (LG) staining, Schirmer I test with anaesthesia (ST) and the ocular-surface disease index (OSDI) questionnaire were performed consecutively. Corneal cell densities and sub-basal nerve plexus were evaluated with IVCM (ConfoScan 4, Nidek, Japan). Finally, quantitative MG drop-out assessment was made using infrared meibography. Shapiro Wilk, Friedman’s and Post-hoc Dunn tests were used for the statistical analysis. RESULTS: TBUT, ST scores, basal epithelium, anterior and posterior keratocytes and endothelial cell densities, long and total sub-basal nerve densities were found to be decreased (p

Purpose/objective(s) Metastasis- directed therapy (MDT) utilizing stereotactic body radiotherapy (SBRT) for oligoprogressive lesions could provide a delay in next-line systemic treatment (NEST) change while undergoing androgen receptor-targeted agents (ARTA) treatment. We evaluated prognostic factors for prostate cancer-specific survival (PCSS) and progression-free survival (PFS) to characterize patients receiving treatment with ARTA who may benefit from MDT for oligoprogressive lesions. The impact of MDT on delaying NEST and the predictive factors for NEST-free survival (NEST-FS) were also assessed. Materials/methods The clinical data of 54 metastatic castration-resistant prostate cancer patients with 126 oligoprogressive lesions receiving abiraterone (1 g/day) or enzalutamide (160 mg/day) before or after systemic chemotherapy were analyzed. A median of three lesions (range: 1-5) were treated with MDT. The primary end points were PCSS and PFS. The secondary end points were time to switch to NEST and NEST-FS. Results The median follow-up time was 19.1 months. Univariate analysis showed that the number of oligoprogressive lesions treated with SBRT and the time between the start of ARTA treatment and oligoprogression were significant prognostic factors for PCSS, and the timing of ARTA treatment (before or after chemotherapy) and the PSA response after MDT were significant prognostic factors for PFS. Multivariate analysis showed that early MDT for oligoprogressive lesions delivered less than six months after beginning of ARTA [HR = 3.20 (95% CI, 1.12-9.15); P = 0.03] and higher PSA levels after MDT [HR = 1.01 (95% CI 1.00-1.01), P = 0.02] were significant predictors of worse PCSS and PFS. The median total duration of ARTA treatment was 13.8 months. The median time between the start of ARTA treatment and the start of MDT for oligoprogressive lesions was 5.2 months, and MDT extended the ARTA treatment by 8.6 months on average. Thirty-two (59.3%) patients continued ARTA treatment after MDT. ARTA treatment after chemotherapy, early oligoprogression requiring MDT, and lower radiation doses for MDT were independent predictors of NEST-FS in multivariate analysis. Conclusion MDT for oligoprogressive lesions is effective and may provide several benefits compared to switching from ARTA treatment to NEST. Patients with early progression while on ARTAs and inadequate PSA responses after MDT have a greater risk of rapid disease progression and poor survival, which necessitates intensified treatment.

Purpose The aims of this study were to investigate if/how the presence of lymphedema affects the sensation of the upper limb and to assess whether complex decongestive physiotherapy (CDP) has a favorable impact on sensory testing. Methods A total of 27 patients with unilateral stage 2 breast cancer–related lymphedema (BCRL) were included in the study. Bilateral circumferential measurements were taken with a tape measure at different levels. Based on these measurements, limb volumes were determined by summing segment volumes derived from the truncated cone formula. Circumferential measurements and ultrasonographic evaluations (epidermis, dermis, and subcutaneous fat thicknesses) were performed at 10 cm distal to the elbow crease. The Semmes–Weinstein monofilament (SWM), static and moving two-point discrimination, pressure pain threshold (PPT), and tactile localization tests were also applied at the same site. After an initial evaluation, all patients underwent CDP phase 1 program. All the evaluations were repeated at the end of the treatment period. Results Before CDP, affected sides had significantly higher values than the unaffected sides in terms of SWM (p

Objective Immunocompromised patients are at a greater risk of developing intestinal parasite infections. In this study, we examined the presence of Enterocytozoon bieneusi, Encaphalitozoon intestinalis and other intestinal protozoa in stool samples of immunosuppressed patients. Methods A total of 100 stool samples were obtained from patients receiving chemotherapy because of solid organ tumour with haematological malignancies and those receiving immunosuppressive treatment because of rheumatic diseases, organ transplant patients and patients receiving treatment for HIV-related infections. Stool samples were examined by using the native-lugol method in which the stool concentration, modified Kinyoun acid-fast and trichrome staining methods and parasite presence were analysed. The stool samples were also examined for the presence of Enterocytozoon bieneusi and Encephalitozoon intestinalis using an indirect fluorescent antibody method. Results Intestinal parasites were detected in 12% of all patients. The distribution of intestinal parasites in patients were 7% Blastocystis spp., 2% Blastocystis spp. + Dientamoeba fragilis, 1% Blastocystis spp. + Entamoeba coli, 1% Blastocystis spp. + Giardia intestinalis and 1% G. intestinalis. Microsporidia spp. were detected in 4% of all patients by the IFAT method and in 8% of all patients by calcoflour staining method. Conclusion In our study, the most prevalent parasite detected in the immunosuppressed patients was Blastocystis spp. The pathogenesis of Blastocystis spp. remains to be controversial, and their role in immunocompromised patients continues to remain unknown. Although these rates detected in our study are similar to the prevalence in the normal population, it is important to study these microorganisms in immunocompromised patients in terms of the associated decreasing morbidity and mortality rates.

Introduction Kaposi sarcoma (KS) is an angioproliferative malignancy associated with HHV-8. It is mostly observed in patients affected by HIV and/or chronic immunosuppression, while classic KS without underlying immunosuppression are relatively rare. Systemic chemotherapy is used for advanced diseases, although there is no consensus in treatment algorithms. With the demonstration of PD-1 expression in KS, immune-checkpoint-inhibitors (ICI) emerged as possible treatment options. Notwithstanding, the data of ICIs is limited to case reports/series. Herein, we present a case of advanced classic KS, which has been treated successfully with nivolumab. Case report 82-year-old male patient was investigated for erythematous lesions on thigh. Punch biopsy lead to KS diagnosis. Abdominal CT showed lymphadenopathies in the inguinal region. After radiotherapy follow-up, patient had shown vertebral & gastric metastases. Because of the PSA elevation patient was diagnosed with prostatic adenocarcinoma. Metastases were investigated for origin. The lesions showed no uptake in Ga-68 PET-CT, therefore accepted as KS metastases. Patient rejected chemotherapy options and consented to immunotherapy trial. Management and outcome: Nivolumab was initiated 3 mg/kg bi-weekly with 12-dose protocol. After nivolumab patient wellbeing is improved and control endoscopy shown no metastases. With these findings patient has been assessed as complete response. Discussion ICI on KS is still a blurred option to be included in standard regimens; but progressive understanding of PD-1 expression and its role in disease progression may be a milestone for further treatment algorithms on KS. Besides good efficacy, tolerability of ICIs could be helpful patients with comorbidities precluding the use of chemotherapy.

Introduction Testicular germ cell tumors (GCT) are the most common tumor in young men. Their distinctive feature is the exceptional response to platin based combination chemotherapy.Since the prognosis is poor in relapsed and refractory patients, the immune checkpoint inhibitors are candidate agents in these patients although clinical trials are mostly lacking. Herein, we describe a patient with a refractory nonseminomatous GCT using nivolumab as a last resort therapy and provided long term response without any significant toxicity. Case report A 41-year-old male presented with the complaint of flank pain eleven years ago. The patient underwent a retroperitoneal lymph node excision and pathology reported as the mixed germ cell tumor. There were no mass in the testicles and the patient was diagnosed with a primary retroperitoneal GCT. Since the disease has progressed under multiple lines of chemotherapy and autologous stem cell transplantation, treatment was started with nivolumab. Management and outcome The patient started to treatment with nivolumab 3 mg/kg two weekly as a last resort treatment. The nivolumab was continued and the patient's response to this treatment is ongoing and has been stable for 13 months. Discussion There are limited treatment options in platinum-refractory germ cell tumors. Recently, immune checkpoint inhibitors tried in this setting with some success in especially non-seminomatous GCTs. We see a good response and prolonged benefit with the use of nivolumab in our patient. Further research including prospective studies on the use of immune checkpoint inhibitors in platinum-resistant testicular cancer can further delineate the role of immunotherapy.

Chemoresistance is a major obstacle in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. Here we identify hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key inducer of chemoresistance by developing chemoresistant TNBC tumors in vivo and characterizing their transcriptomes by RNA-sequencing. Inhibiting LOX reduces collagen cross-linking and fibronectin assembly, increases drug penetration, and downregulates ITGA5/FN1 expression, resulting in inhibition of FAK/Src signaling, induction of apoptosis and re-sensitization to chemotherapy. Similarly, inhibiting FAK/Src results in chemosensitization. These effects are observed in 3D-cultured cell lines, tumor organoids, chemoresistant xenografts, syngeneic tumors and PDX models. Re-expressing the hypoxia-repressed miR-142-3p, which targets HIF1A, LOX and ITGA5, causes further suppression of the HIF-1α/LOX/ITGA5/FN1 axis. Notably, higher LOX, ITGA5, or FN1, or lower miR-142-3p levels are associated with shorter survival in chemotherapy-treated TNBC patients. These results provide strong pre-clinical rationale for developing and testing LOX inhibitors to overcome chemoresistance in TNBC patients., The development of chemoresistance is a major hurdle in triple negative breast cancer (TNBC). Here, the authors show that lysyl oxidase (LOX) is overexpressed in chemoresistant TNBCs, and when inhibited reduces collagen cross-linking, fibronectin fibril assembly, and downstream integrin signalling, overcoming resistance.

Introduction: Breast cancer is the most common cancer in women and is the second most common cause of cancer related mortality. Metabolomics, the identification of small metabolites, is a technique for determining the amount of these metabolites. Objectives: This study aimed to identify markers for the early diagnosis of brain metastasis by metabolomic methods in breast cancer patients. Methods: A total of 88 breast cancer patients with distant metastases were included in the study. The patients were divided into two groups according to their metastasis status: patients with brain metastases and distant metastases without any brain metastases. Liquid chromatography quadrupole time-of-flight mass spectrometry (LC-qTOF-MS) and gas chromatography-mass spectrometry (GC-MS) analysis methods were used for metabolomic analyses. Results: 33 of them, 88 patients had brain metastasis, and 55 patients had distant metastases without brain metastasis. A total of 72 and 35 metabolites were identified by the GC-MS and LC-qTOF-MS analysis, respectively. 47 of them were found to be significantly different in patients with brain metastasis. The pathway analysis, performed with significantly altered metabolites, showed that aminoacyl tRNA biosynthesis, valine, leucine and isoleucine biosynthesis, alanine, aspartate, and glutamate metabolism, arginine biosynthesis, glycine, serine, and threonine metabolism pathways significantly altered in patients with brain metastasis. Predictive accuracies for have identifying the brain metastasis were performed with receiver operating characteristic (ROC) analysis, and the model with fifteen metabolites has 96.9% accuracy. Conclusions: While these results should be supported by prospective studies, these data are promising for early detection of brain metastasis with markers in liquid biopsy samples.

The combination of cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitors plus endocrine therapy (ET) improved the survival outcomes and became the standard of care in the treatment of metastatic hormone-positive breast cancer. However, these combinations increased the risk of neutropenia compared with ET alone. While the infection-related mortalities did not seem to be increased, the exact risk of infections with CDK 4/6 inhibitor and ET combinations is relatively understudied. Therefore, we performed a meta-analysis of CDK 4/6 inhibitor clinical trials to assess the infection risk of adding CDK4/6 inhibitors to ET.We systemically searched the PubMed database for relevant clinical trials. For each study, all grade and grade 3 or higher infections, upper respiratory tract infections (URTI), urinary tract infections (UTI), pneumonia, and febrile neutropenia rates were recorded whenever available. The hazard ratios (HR) with a 95% confidence interval (CI) of infection risk were calculated via the generic inverse-variance method with a random-effects model.Nine eligible studies were included in the analyses (MONALEESA-2,3,7, MONARCH-2,3, MONARCH plus, PALOMA-1,2,3). In the meta-analysis of these studies, CDK 4/6 inhibitors plus ET arms were associated with increased all grade infections (HR 1.77, 95% CI 1.56-2.01, p 0.00001), grade 3 or higher infections, (HR 1.77, 95% CI 1.28-2.43, p = 0.0005), UTIs (HR 1.59, 95% CI 1.19-2.12, p = 0.002), and febrile neutropenia (HR 4.28, 95% CI 1.73-10.62, p = 0.002).In this meta-analysis, we observed that adding CDK4/6 inhibitors to ET significantly increased the risk of all grade, grade 3 or higher infections, and urinary tract infections. We propose that closer follow-up for infections should be considered for metastatic breast cancer patients using CDK 4/6 inhibitors. This may help clinicians to recognize infections earlier which prevents early death from infection.

BACKGROUND: The albumin-globulin ratio (AGR) could be a prognostic biomarker in patients with cancer, although the data is limited in patients treated with immune-checkpoint inhibitors (ICIs). OBJECTIVES: We aimed to evaluate the association between AGR and survival in ICI-treated patients. METHODS: The data of 212 advanced-stage patients were retrospectively evaluated in this cohort study. The association between AGR with overall (OS) and progression-free survival (PFS) were evaluated with multivariate analyses. Additionally, receptor operating curve (ROC) analysis was conducted to assess the AGR’s predictive power in the very early progression (progression within two months) and long-term benefit (more than twelve months survival). RESULTS: The median AGR was calculated as 1.21, and patients were classified into AGR-low and high subgroups according to the median. In the multivariate analyses, patients with lower AGR (< 1.21) had decreased OS (HR: 1.530, 95% CI: 1.100–2.127, p= 0.011) and PFS (HR: 1.390, 95% CI: 1.020–1.895, p= 0.037). The area under curve of AGR to detect early progression and long-term benefit were 0.654 (95% CI: 0.562–0.747, p= 0.001) and 0.671 (95% CI: 0.598–0.744, p< 0.001), respectively. CONCLUSIONS: In our experience, survival with ICIs was impaired in patients with lower AGR. Additionally, the AGR values could detect the very early progression and long-term benefit ICIs.

The immune checkpoint inhibitors (ICIs) entered treatment algorithms in most tumors. However, the data on the efficacy is limited in rare tumors with no phase III studies. We systemically reviewed the clinical trials evaluating the ICI efficacy in rare tumors and included a total of 47 clinical trials in this review. The ICIs demonstrated over 30% response rates in Merkel cell carcinoma and squamous cell carcinoma of the skin and became the standard of care. Additionally, the ICI efficacy was promising in thymic epithelial tumors and gestational trophoblastic neoplasia. In contrast, the ICI efficacy is limited in most sarcomas, germ cell tumors and low-grade neuroendocrine tumors. The ICI efficacy seemed to be improved with combinations targeting tumor microenvironment in sarcomas. The available evidence on ICI efficacy in rare tumors denote a need for better patient selection and novel combination strategies to improve outcomes.

Background: In node-negative HER2-overexpressed breast cancers, adjuvant paclitaxel plus trastuzumab treatment is a successful de-escalation approach with excellent survival outcomes. Methods: All patients with HER2+ breast cancer treated in our centers were retrospectively reviewed. Results: We analyzed 173 patients who were treated with adjuvant paclitaxel plus trastuzumab. The mean tumor size was 2.2 cm. There were eight invasive disease events or death: four distant recurrences (2.3%), three locoregional recurrences (1.7%) and one death without documented recurrence after a 52 month follow-up. The 3-year disease-free survival and recurrence-free interval rate was 96.6%. Conclusion: This real-life experience with adjuvant paclitaxel plus trastuzumab demonstrated few distant recurrences and is compatible with the APT trial findings.

The objective of the present study was to compare the efficacy of axitinib and nivolumab in metastatic renal cell carcinoma (mRCC) previously treated with targeted therapy.A total of 79 patients were enrolled (39 patients in axitinib group, 40 patients in nivolumab group). Survival outcomes of patients, progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier method and compared with the log-rank test. The associations between potential prognostic variables and OS were evaluated in univariate and multivariate Cox regression analyses.The median PFS and OS of all cohort were 8.1 and 36.6 months, respectively. Higher PFS and OS were evaluated in axitinib group than nivolumab group (PFS: 9.4 months vs 6.3 months, p=0.386; OS: 38.2 months vs 36.6 months, p=0.671, respectively). Patients treated with axitinib had numerically higher objective response rate (ORR) and disease control rate (DCR) than those treated with nivolumab (ORR: 43.6% vs 27.6%, p=0.157, DCR: 74.4% vs 62.5%, p=0.157, respectively). Multivariate analysis revealed that the independent predictors of OS were higher tumor grade (hazard ratio [HR]: 6.178, p=0.004), worse response to axitinib and nivolumab (HR:4.902, p=0.011), the presence of lung metastasis (HR:15.637, p=0.002) and the presence of liver metastasis (HR:12.010, p=0.001).Comparable survival outcomes were detected in the axitinib and nivolumab groups. However, head to head comparisons are needed to highlight the relative efficacy of these therapies in mRCC.

The immune checkpoint inhibitors have opened new horizons in oncology. Although the indications for the use of Immune checkpoint inhibitors in cancer patients are expanding, there is still a need for markers that can aid in patient selection. Gastrointestinal microbiota can be among these markers. Recently, gastrointestinal microbiota stated to have a bidirectional relation with cancer immunotherapy with roles in both prognostic and therapeutic sides. Preclinical data suggest that modulation of the microbiota could become a novel strategy for improving the efficacy of immunotherapy. However, its labile structure prone to be affected by many factors. Further research can delineate the mechanisms of the relationship between microbiota and immunotherapy can have clinical implications.

BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], pINTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.FUNDING: Merck Sharp & Dohme.

Recently, neoadjuvant treatment approach has gained importance in locally advanced HER-2 positive breast cancer. Adding pertuzumab increases pathological complete response (pCR). In this study, we aimed to examine the clinicopathologic features that predict the pCR in patients receiving neoadjuvant pertuzumab, trastuzumab, and chemotherapy in locally advanced HER2 positive breast cancer.Locally advanced HER2 positive breast cancer patients who were followed up in 4 different oncology centers and received 4 cycles of pertuzumab, trastuzumab and taxane were retrospectively evaluated. A total of 58 (92%) patients received anthracycline chemotherapy before combination of dual her-2 blockade and taxanes. Fisher's and chi-square tests were used for nominal variables and numeric data analyses.A total of 63 female patients were included in the study. Their median age was 46 years (21-75) and 40 (63.5%) patients were premenopausal. Median tumor size was 25 mm (2-70) and there were 22 (34.9%) patients with Stage 3a. pCR was 66% and 75% in the whole group and in the hormone negative group, respectively. Statistically significant increase was found in pCR in patients with grade 3 tumors and cerbB2 with 3+ immunohistochemical staining. No relationship was found between pCR and age at diagnosis, menopausal status, tumor infiltrating lymphocyte, dose-dense anthracycline, Ki67≥40, body mass index (BMI) ≥ 30 kg/m2 and accompanying DCIS.Four cycles of pertuzumab, trastuzumab and taxane after neoadjuvant anthracycline for locally advanced HER2 breast cancer are associated with increased pCR in patients with grade 3 tumors and high cerbB2 expression.

Background The association of thrombospondin type 1 domain-containing 7A (THSD7A) expression, a novel angiogenesis-related marker, with survival outcomes of tumors including renal cell carcinoma (RCC) remains to be clarified. Therefore, we investigated the impact of THSD7A on outcomes of metastatic RCC (mRCC) patients treated with targeted therapy. Methods A total of 86 mRCC patients were included. The expression of THSD7A in nephrectomy material of the patients was assessed by immunohistochemistry and expression patterns were categorized into two groups: negative (no staining) and positive. Univariable and multivariable Cox regression models evaluated the impact of THSD7A expression on progression free survival (PFS) and overall survival (OS) of the patients. Results THSD7A expression was determined in 77.9% of the patients. Kaplan-Meier analyses showed that while the patients with THSD7A expression had significantly inferior OS times than those with negative THSD7A expression (19.9 months vs. 52.2 months, P = 0.024, respectively), there was no association between THSD7A expression and PFS. The univariate analyses demonstrated that the significant variables in predicting OS were presence of bone metastasis (P = 0.030), THSD7A expression (P = 0.028), and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) scoring system (P < 0.001). However, applying multivariate analyses, the independent variables in predicting OS were THSD7A expression (HR: 2.639, P = 0.037) and IMDC scoring system (P < 0.001). Conclusion We revealed that THSD7A expression was associated with OS of mRCC patients treated with targeted therapy. There might be an important link between THSD7A expression and resistance to targeted therapy.

Introduction Polypharmacy is a common problem in older cancer patients, although the data about polypharmacy and potentially inappropriate prescription practices is limited in patients treated with immune checkpoint inhibitors (ICIs). Therefore, we aimed to evaluate the polypharmacy frequency and drug-drug interactions in older cancer patients (≥65 years) treated with ICIs. Methods A total of 70 geriatric patients with advanced cancer were included. The polypharmacy was defined as regular use of 5 or more drugs. The START/STOPP Criteria Version 2 was used for the potentially inappropriate medications (PIM) and potential prescription omissions (PPO). The Medscape Drug Interaction Checker was used for potential drug-drug interactions. Results The patients had a median of 6 regular drugs, and polypharmacy was present in 77.1%. The polypharmacy risk was significantly increased in patients over 75 years of age (p = 0.028) and with opioid use (p = 0.048). The 50% of patients had category D or X interactions. Patients with higher Charlson Comorbidity Index had significantly increased risk for drug interactions (CCI ≤10 vs. >10, p = 0.017). The PIMs were present in 44.3% and the PPOs in 68.6% of the patients. While the overall survival and immune related adverse events were similar according to polypharmacy, in patients using seven or more drugs, the acute kidney injury risk was increased (HR: 4.667, p = 0.038). Conclusion In this study, we observed a high rate of polypharmacy and inappropriate prescription practices in ICI-treated patients. These issues pointed out the need for improved general medical care and attention for better comedication management in ICI-treated patients.

Background This study was conducted to collect clinical safety, tolerability, and efficacy data with the use of everolimus (EVE) combined with exemestane (EXE) in patients with advanced breast cancer (ABC). Methods The EVEREXES trial initiated in 2012, provided early access to the first dual blockade treatment with EVE + EXE in patients with HR+, HER2 - ABC in Asia and other emerging growth countries. Postmenopausal women with HR+, HER2 - ABC who had documented recurrence or progression, following a nonsteroidal aromatase inhibitor therapy, were treated with EVE (10 mg/day) + EXE (25 mg/day) orally. Results A total of 235 patients received >= 1 dose of study medication. At the end of the study, all patients ceased the treatment. Disease progression (66.0%) was the primary reason of discontinuation. The most common AEs (>= 20%) were stomatitis, decreased appetite, hyperglycemia, rash, aspartate aminotransferase increased, anemia, alanine aminotransferase increased, cough, and fatigue. No new safety concerns were identified in the current study. Median progression-free survival (PFS) in the Asian subset was similar to that of the overall population (9.3 months in both groups). Confirmed overall response rate (ORR) was achieved for 19.6% of the patients. Efficacy of EVE + EXE across subgroups (prior CT, line of treatment, and presence of visceral metastases) was maintained. Conclusion The safety and efficacy results from EVEREXES trial are consistent to data previously reported in BOLERO-2. These results support that EVE + EXE could be a viable treatment option for the postmenopausal women with HR+, HER2 - ABC in Asian region., Novartis Pharma AG, Base, Switzerland; NovartisNovartis, The EVEREXES trial was funded by Novartis Pharma AG, Base, Switzerland. Funding for medical editorial support was also provided by Novartis.

Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in cancer patients. However, the association of VTE with immunotherapy remains poorly defined. We therefore evaluated the frequency of VTE in patients receiving immunotherapy and tried to determine predisposing factors. A total of 133 adult metastatic cancer patients treated with immunotherapy for any cancer between were included. Baseline demographics, ECOG performance status, type of tumors, and baseline blood count parameters were recorded. Possible predisposing factors were evaluated with univariate and multivariate analyses. The median age was 60 (interquartile range (IQR) 48–66) years, and the median follow-up was 10.1 (IQR 5.8–18.5) months. Renal cell carcinoma (26.3%) and melanoma (24.1%) were most common diagnoses. Fifteen patients (11.3%) had an episode of VTE. Most of the VTEs were diagnosed as pulmonary emboli (10/15; 67%). Eighty percent (12/15) of these VTE cases were detected incidentally. Patients with a baseline ECOG performance status of 1 or more (29.3% of patients) had a significantly increased risk of venous thrombosis (ECOG ≥1 vs. 0, HR: 3.023, 95% CI: 1.011–9.039, p=0.048). Other factors, including patient age, tumor type, body mass index, baseline thrombocyte, neutrophil, and lactate dehydrogenase levels were not significantly associated with VTE risk. In this study, we observed VTE development in more than 10% of immunotherapy-treated patients and increased VTE risk in patients with poorer ECOG status. With the asymptomatic nature of VTEs in most cases, a high index of suspicion level for VTE is required in patients treated with immunotherapy.

BACKGROUND/AIM We aimed to evaluate the efficacy of fulvestrant and affecting clinical factors, including the optimal sequencing of fulvestrant and chemotherapy in a real-life cohort. METHODS The data of 256 metastatic hormone-positive breast cancer patients treated with fulvestrant were evaluated. The association of clinical factors with survival was analyzed with Kaplan-Meier and Cox-regression analyses. RESULTS The median age of patients was 57 years. More than half of the patients used fulvestrant in later lines and after chemotherapy (75.8%). The median progression-free (PFS) and overall survival (OS) of all cohort were 6.05+/-0.56 and 29.70+/-1.61 months, respectively. Primary endocrine resistance (HR: 1.989, 95% CI: 1.430-2.766

Although the immune checkpoint inhibitors (ICIs) became a vital part of cancer care, many patients do not respond to treatment, indicating need for biomarkers. The Pan-Immune-Inflammation Value (PIV) is a recently developed peripheral blood count-based biomarker. Herein, we evaluated a PIV-based candidate scoring system as a prognostic biomarker in ICI-treated patients.A total of 120 advanced cancer patients treated with anti-PD-1 or anti-PD-L1 inhibitors for any cancer type were included in this study. The PILE scoring system incorporating the PIV ( median vs. ≥ median), lactate dehydrogenase levels (normal vs. normal) and Eastern Cooperative Oncology Group performance status (0 vs. ≥ 1) was constructed from the multivariate analyses and used for stratification. The association between overall survival (OS), progression-free survival and PILE risk category was evaluated with multivariate analysis.The median follow-up was 9.62 months and the median OS of all cohort were 12.42 ± 2.75 months. Patients with higher PIV had significantly decreased OS (7.75 ± 1.64 vs. 18.63 ± 4.26 months, p = 0.037). The patients in the PILE high-risk group (PILE score 2-3) had decreased OS (18.63 ± 4.02 vs. 5.09 ± 1.23 months, HR: 2.317, 95% CI: 1.450-3.700, p 0.001) and PFS (7.69 ± 1.30 vs. 2.69 ± 0.65 months, HR: 1.931, 95% CI: 1.263-2.954, p = 0.002) compared to PILE low-risk group (PILE score 0-1). The Harrell C-Index values were 0.65 and 0.61 for OS and PFS prediction, respectively.In this study, we demonstrated a decreased overall survival in ICI-treated patients with a higher PILE score. If prospective studies validate our results, PILE score could be a biomarker for immunotherapy.

Background In the phase III OlympiAD trial, olaparib significantly increased progression-free survival (PFS) compared with chemotherapy of physician's choice in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (mBC). The phase IIIb LUCY trial assessed the clinical effectiveness of olaparib in similar patients, in a setting reflecting clinical practice. Methods This open-label, single-arm trial of olaparib (300 mg, twice daily) enrolled patients with BRCAm, HER2-negative mBC who had received taxane and/or anthracycline in the (neo)adjuvant/metastatic setting and not more than two lines of prior chemotherapy for mBC. Patients with hormone receptor–positive mBC had progressed on at least one line of endocrine therapy in an adjuvant/metastatic setting and were unsuitable for further endocrine treatment. This interim analysis was planned after 160 PFS events. Results Of 563 patients screened, 252 patients with gBRCAm were enrolled and received at least one dose of olaparib. The median investigator-assessed PFS was 8.11 months (95% confidence interval [CI], 6.93–8.67; 166/252 events [65.9% maturity]). The investigator-assessed clinical response rate was 48.6%, and median time to first subsequent treatment or death was 9.66 months (95% CI, 8.67–11.14). The most common treatment-emergent adverse events (TEAEs; >20% patients) were nausea, anaemia, asthenia, vomiting and fatigue. Eleven patients (4.4%) discontinued treatment because of a TEAE. Grade 3 or higher TEAEs occurred in 64 patients (25.4%), including anaemia (33 patients; 13.1%). Conclusion Olaparib was clinically effective in patients with gBRCAm, HER2-negative mBC with safety outcomes consistent with previous findings. ClinicalTrials.gov identifier: NCT03286842 .

BACKGROUND Health-related quality of life is measured to detect the influence of lymphedema on physical, functional, and social aspects of life in patients with breast cancer-related lymphedema (BCRL). OBJECTIVE This study aimed to perform the psychometric evaluation of the Lymphedema Life Impact Scale (LLIS) in Turkish patients with BCRL. METHODS Patients with BCRL (n = 78) filled out the Turkish LLIS, Lymphedema Quality of Life, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, and Quick Disability of Arm, Shoulder and Hand scales. Breast cancer survivors without BCRL (n = 35) completed only the Turkish LLIS. Psychometric properties were analyzed with the internal consistency, test-rest reliability, construct, criterion, and discriminant validity. RESULTS The internal consistency of the Turkish LLIS was strong (Cronbach's α coefficient >.70). Test-retest reliability was strong to very strong (intraclass correlation coefficients from 0.88 to 0.93; P < .001). Similar to the original structure of the scale, exploratory factor analysis identified 3 factors. Criterion validity was supported by moderate to strong correlations between the LLIS, Lymphedema Quality of Life, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30, and quick Disability of Arm, Shoulder and Hand. There were significant differences in the total and subscale scores of the LLIS between participants with and without BCRL (P < .05). CONCLUSIONS The present study provided the evidence to confirm reliability and clinical validity of the Turkish LLIS. IMPLICATIONS OF PRACTICE The Turkish LLIS is a reliable and valid condition-specific scale to measure the physical, functional, and psychological aspects of health-related quality of life in patients with BCRL.

The emergency department (ED) is a crucial encounter point in cancer care. Yet, data on the causes of ED visits are limited in patients treated with immune checkpoint inhibitors (ICI). Therefore, we evaluated ED visits in patients treated with ICIs in attempt to determine the predisposing factors. We performed a retrospective chart review on adult cancer patients treated with ICIs for any type of cancer in the Hacettepe University Cancer Center. The data on ED visits after the first dose of ICIs to 6 months after the last cycle of ICIs were collected. A total of 221 patients were included in the study. The mean age was 58.46 ± 13.87 years, and 65.6% of patients were males. Melanoma was the most common diagnosis (27.6%), followed by kidney and lung cancers. Eighty-three of these patients (37.6%) had at least one emergency department (ED) visit. Most of the ED visits were related to symptoms attributable to the disease burden itself, while immune-related adverse events comprised less than 10% of these visits. While baseline Eastern Cooperative Oncology Group performance status, age, polypharmacy, concomitant chemotherapy, eosinophilia, and lactate dehydrogenase levels did not significantly increase the risk, patients with regular opioid use and baseline neutrophilia (> 8000/mm3) had a statistically significant increased risk of visiting the ED (p = 0.001 and 0.19, respectively). These two factors remained significant in the multivariate analyses. In this study, almost 40% of ICI-treated patients had ED visits. Collaboration with other specialties like emergency medicine is vital for improving the care of patients receiving immunotherapy.

Current treatment guidelines for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) recommend multimodal treatment, including chemoradiation therapy (CRT) or surgery followed by radiation, with or without chemotherapy. The immune checkpoint inhibitor pembrolizumab has previously demonstrated antitumor activity in recurrent and/or metastatic HNSCC in large Phase III trials. For patients with locally advanced disease, Phase Ib data on the use of pembrolizumab in combination with chemoradiation have shown the approach to be safe and feasible. We describe here the design and rationale for KEYNOTE-412, a randomized, double-blind, Phase III trial investigating pembrolizumab or placebo administered concurrently with CRT and as maintenance treatment in patients with locally advanced HNSCC. Clinical Trial Registration: NCT03040999 ( ClinicalTrials.gov ).

Purpose To evaluate the potential benefit of curative radiotherapy (RT) to the primary tumor in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone. Materials and methods The clinical parameters of 106 mCRPC patients treated with abiraterone were retrospectively evaluated. Patients were either oligometastatic (= 50% of the baseline obtained 3 weeks after abiraterone therapy was the only significant prognostic factor for better OS and progression-free survival (PFS). Patients treated with primary RT to the prostate had significantly less progression under abiraterone and a longer abiraterone period than those treated without local prostate RT. Conclusions Local prostate RT significantly improved OS and local control in mCRPC patients treated with abiraterone. The patients treated with primary RT had significantly less progression under abiraterone and a longer abiraterone period than those treated without local prostate RT.

In metastatic and recurrent head and neck cancer (M/R HN-SCC), the median survival is less than a year and locoregional recurrence is the main cause of death. Our aim was to evaluate the results of concurrent stereotactic body radiotherapy (SBRT) and immunotherapy (ICI) in these patients.Fifteen patients diagnosed with M/R HN-SCC were evaluated retrospectively. All patients received SBRT (3x8 Gy) to all recurrent and metastatic foci with concurrent ICI.Six months overall survival (OS) rates and progression-free survival (PFS) rates were 93% and 86%, respectively. Local control (LC) rate in the site of SBRT was 96%. Higher survival and LC rates were achieved with lower doses of radiotherapy with the synergistic effect of SBRT and ICI.Concurrent ICI and SBRT was feasible with excellent LC.

Background Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. Patients and methods In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8mg/kg loading dose, then 6mg/kg every 3weeks (q3w)] and pertuzumab (840mg loading dose, then 420mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). Results Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54years; 29% had received prior trastuzumab. Median treatment duration was 16months for pertuzumab and trastuzumab and 4months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9–22.7] months overall (19.6, 23.0 and 18.1months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%–82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). Conclusions Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. ClinicalTrials.gov NCT01572038.

Modified docetaxel, cisplatin, and 5-fluorouracil (mDCF) therapy has been shown to be a well tolerated and highly effective regimen for metastatic gastric carcinoma. Herein we investigated the effectiveness of the mDCF combination as the first-line treatment in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (HNSCC).A total of 80 patients with recurrent/metastatic HNSCC who were treated with mDCF between 2009 and 2015 were enrolled into this study. All patients were treated in the first-line with 2-6 cycles of mDCF chemotherapy which consisted of docetaxel 60 mg/mThe most common grade 3-4 toxicities were neutropenia (22.5%), anemia (10%), thrombocytopenia (7.5%), nephrotoxicity (1.3%), hepatotoxicity (1.3%), and diarrhea (2.5%). Twelve patients (15%) experienced a febrile neutropenic episode. Dose modification was required in 22 (27.5%) of the patients due to drug toxicity. Complete response was achieved in 2.5% of all patients, while partial and stable responses were reported to be 43.8% and 25%, respectively, with a disease control rate of 71.3%. The median progression-free and overall survival was 7 (95% CI: 5.3-8.6) and 11.5 (95% CI: 9.4-13.7) months, respectively.The efficiency of the mDCF combination for induction chemotherapy has been well established previously. To our knowledge, this is one of the largest studies evaluating the survival and safety significance of mDCF chemotherapy as a first-line treatment in patients with recurrent/metastatic HNSCC.

Introduction: The relation between Behçet's disease (BD) and breast cancer (BC) is unclear. Our purpose is to investigate whether BD has an important effect on BC or vice versa. Patients and Methods: A total of 12 female BC patients with a diagnosis of BD were identified from a cohort including 5050 BC patients. The demographic data of the selected patients including previous chemotherapy (CT), radiotherapy (RT), hormonal therapy (HT), drugs used for BD, history of thrombotic events, and overall survival were examined. Results: The rate of BD in the entire cohort was found to be 0.25% (12/4800), and all had early BC at the time of BC diagnosis, with a median age of 47 years (range: 38–51). All patients underwent curative surgery for BC. In the adjuvant setting, CT, RT, and HT were administered in 11 (91%), 10 (83.4%), and 9 (75%) patients, respectively. All patients received acetylsalicylic acid and colchicine for BD. No serious adverse event associated with BC and/or BD was observed. Clinical symptoms in 11 patients with BD were observed to be improved following the BC treatment. Only one patient developed disease progression and then expired. Conclusion: Unlike the natural behavior of BD, which is well-defined to have an increased risk of thrombosis, BC patients with BD in this study did not have any adverse event. However, due to small sample size, it is difficult to drive any definite conclusion regarding the relation between these two pathologies.

Denosumab is fully human monoclonal antibody that specifically binds and inactivates receptor activator of NF-kB ligand (RANKL), an important ligand that regulates bone remodeling. In this review, we aimed to show the clinical data about denosumab treatment and discuss its advantages for the management of patients with solid tumors and bone metastasis.Denosumab showed positive results in clinical studies of solid tumors with bone metastasis. PubMed database and ASCO Symposium Meeting abstracts were searched until August 2015 by using the terms 'denosumab', 'RANKL inhibitor' and 'bone metastasis'. The last search was on 21 August 2015. All resulting studies were retrieved and were also checked for related publications. Clinical trials in this review fulfilled the following criterion: inclusion of sufficient data to allow estimation of the efficacy and safety of denosumab.The effects of denosumab on skeletal-related events (SREs) were investigated in three large randomized trials: one in patients with breast cancer, one in patients with prostate cancer, and one in patients with multiple myeloma or solid tumors other than breast or prostate cancer. In the breast cancer and prostate cancer studies denosumab was non-inferior and also superior to zoledronic acid in terms of the primary outcome time to first on-study SRE. In the third study denosumab was non-inferior to zoledronic acid but was not superior to zoledronic acid in solid tumors excluding breast and prostate cancer with bone metastases. In the three studies median overall survival and disease progression rates were similar between zoledronic acid and denosumab. Denosumab has also been studied in bone loss associated with hormonal therapy in both breast and prostate cancer. Adjuvant denosumab significantly reduced the risk of clinical fracture risk by 50% in breast cancer patients and by 62% in non-metastatic prostate cancer patients treated with adjuvant aromatase inhibitors or androgen deprivation therapy. In addition, biochemical markers of bone turnover and fractures were significantly reduced in patients under denosumab treatment.The promising outcomes in the initial trials with denosumab have shown clinical activity and a favorable safety profile in patients with solid tumors and bone metastasis. Denosumab significantly reduced treatment-related osteoporosis associated with breast and prostate cancer and was superior to zoledronic acid in prevention or delaying of SRE.

Background: The standard treatment of local advanced nasopharyngeal cancer is chemoradiotherapy. There is a lack of data concerning induction therapy. In this study we retrospectively examined patients treated with induction therapy and chemoradiotherapy. Materials and Methods: Locally advanced nasopharyngeal cancer patients treated between 1996 and 2013 in our clinic were included in the study. Three different induction regimens were administered to our patients in different time periods. The regimen dosages were: CF regimen, cisplatin 50mg/m 2 1-2 days, fluorouracil 500mg/m 2 1-5 days; DC, docetaxel 75mg/m 2 1 day, cisplatin 75mg/m 2 1 day; and DCF, docetaxel 75mg/m 2 1 day, cisplatin 75mg/m 2 1 day, 5-Fu 750mg/m 2 1-5 days. Most of the patients were stage III (36.4%) and stage IV (51.7%). Results: Median follow-up time was 50 months (2-201 months). Three-year progression-free survival (PFS) was 79.3%, and 5-year PFS 72.4% in all patients. Three-year overall survival (OS) was 87.4% and 5-year OS 76% in all patients. In terms of induction therapies, 3-year OS was 96.5% in the DCF group, 86.6% in the DC group and 76.3% in the CF group (p=0.03). Conclusions: There was no significant differences in response rate and PFS between the three regimens. OS in the DCF group was significantly higher than in the other groups. However, this study was retrospective and limited toxicity data were available; the findings therefore need to be interpreted with care.

Background In this study, we aimed to assess the prognostic performance of determining the T stage according to the total size of lesions compared with the size of the largest lesion in the breast in patients with multifocal/multicentric (MF/MC) breast cancer. Patients and Methods The charts of the patients with MF/MC breast cancer who were diagnosed between 2003 and 2014 were reviewed. The T stage of MF/MC tumors was determined according to the largest lesion size (Tmax) as well as the sum of the longest diameters of the lesions (Tsum) in the breast. Results Multifocal/multicentric tumors were identified in 323 of 3890 patients (8.3%) with breast cancer. Ten-year rates of overall survival (OS; 75% and 74%; P = .965) and disease-free survival (DFS; 66% and 61%; P = .817) were similar in patients with unifocal and MF/MC tumors, respectively. When the T stage was determined by summing the sizes of the lesions, the T stage of 67 (20.7%) and 63 (19.5%) patients advanced from T1 to T2 and from T2 to T3, respectively. Thus, the T stage increased in 130 patients (40.2%) according to American Joint Committee on Cancer. Discriminatory ability of Tsum was better than Tmax in terms of OS and DFS, as shown with higher Royston D and Harrel C statistics and Schemper V values. Conclusion The new T classification proposed in this report stands out as a better predictive classification particularly in patients with low disease burden.

Trastuzumab is the first anti-HER-2 humanized monoclonal antibody. The benefit of adjuvant trastuzumab has been shown in randomized phase III trials. Despite trastuzumab being recommended for 52 weeks in the adjuvant treatment of HER-2 positive breast cancer according to the current breast cancer guidelines, there is still no consensus on the optimal duration of adjuvant trastuzumab. The aim of our study is to investigate the efficacy and safety of adjuvant trastuzumab for 9 weeks and 52 weeks in axillary lymph node positive HER-2 positive breast cancer patients.A total of 271 HER-2 and axillary node positive breast cancer patients who received trastuzumab in adjuvant treatment between the years 2005 and 2013 were retrospectively analyzed. Patients with axillary node positive HER-2 positive breast cancer who were non-metastatic were enrolled to the study. Patients were allocated to the 9 week trastuzumab group (n = 155) or the 52 week trastuzumab group (n = 116). Kaplan-Meier survival analysis was carried out for disease free survival (DFS) and overall survival (OS). Two-sided p values of0.05 were considered statistically significant. The most important limitation of our manuscript is the retrospective design.The median follow-up time for this analysis was 34 (4-95) months. Patients' clinical and pathological characteristics were well balanced between the two treatment arms. In the 9 week trastuzumab treatment group, the DFS rate was 96.7%, 84.8% and 74.9% in the first, third and fifth years respectively, whereas in the 52 week trastuzumab treatment group it was 94.3%, 80.0% and 80.0% (P = 0.76). In the 9 week trastuzumab treatment group, the OS rate was 99.3%, 92.2% and 88.3% in the first, third and fifth years respectively, whereas in the 52 week trastuzumab treatment group it was 99.0%, 94.7% and 78.6% (P = 0.99). In both groups, symptomatic heart failure was not reported but asymptomatic left ventricular ejection fraction (LVEF) decline was observed 3 (1.9%) and 18 (15.5%) patients in the 9 week and 52 week trastuzumab treatment groups, respectively (P0.001).In our study, the efficacy of trastuzumab for 52 weeks and 9 weeks was similar in node-positive HER-2 positive breast cancer. Cardiotoxicity was significantly increased in the 52 week trastuzumab arm compared to the 9 week trastuzumab arm.

Purpose Excision repair cross-complementation group 1 enzyme (ERCC1) plays a key role in the removal of platinum induced DNA adducts and cisplatin resistance. Prognostic role of ERCC1 expression in the neoadjuvant setting in bladder cancer has not been reported before. We evaluated the prognostic role of ERCC1 expression in bladder cancer receiving platinum-based neoadjuvant chemotherapy. Materials and methods Thirty-eight patients with muscle invasive bladder cancer who received neoadjuvant platinum-based chemotherapy were included. Clinical and histopathologic parameters along with immunohistochemical ERCC1 staining were examined and correlated with response rates and survival. Results Pathologic complete response rates were similar between patients with low and high ERCC1 expression. Median disease-free survival (DFS) was 9.3 vs. 20.5 months ( P = 0.186) and median overall survival (OS) was 9.3 vs. 26.7 months ( P = 0.058) in patients with high ERCC1 expression compared with those with low expression, respectively. In multivariate Cox regression analysis: pathological complete response (pCR) after chemotherapy (hazard ratio (HR) 0.1, 95% CI 0.012–0.842, P = 0.034) and high ERCC1 expression (HR 3.7, 95% CI 1.2–11.2, P = 0.019) were significantly associated with DFS. Patient age (>60 vs. ≤60 years) (HR 3.4, 95% CI 1.2–9.4, P = 0.018), the presence of pCR (HR 0.11, 95% CI 0.014–0.981, P = 0.048) and high ERCC expression (HR 6.1, 95 CI 1.9–19.9, P = 0.002) were significantly associated with OS. Conclusions Our results showed that high ERCC1 expression was independently associated with shorter disease-free and overall survival in patients with bladder cancer who received neoadjuvant platinum-based chemotherapy. ERCC1 may represent a potential predictive marker for platinum-based treatment in bladder cancer.

Breast cancer cells can develop resistance to standard hormonal treatment and chemotherapy with the activation of the mTOR pathway; this is supported by results of preclinical and clinical studies. In clinical trials, the addition of everolimus to hormonal treatment or anti-HER2 treatment improved the outcomes of breast cancer patients. The aim of this review is to discuss the efficacy and safety data of everolimus in all categories of breast cancer in recent published studies.Everolimus showed positive results in clinical studies. A literature search was made from PubMed, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts by using the following search key words: 'everolimus', 'RAD001', 'mTOR inhibitor', 'breast cancer' 'endocrine therapy resistance' and 'HER-2 targeted therapies'. The last search was on June 10, 2013. The most important limitation of our review is that most of the data on everolimus rely on phase I and II trials.Preclinical studies showed that mTOR activation can be the responsible mechanism in all subgroups of breast cancer. Results of both the TAMRAD and BOLERO-2 studies have showed that mTOR inhibition in combination with endocrine therapy can be a new treatment strategy for MBC patients who are resistant to aromatase inhibitors. In the BOLERO-2 study, time to deterioration in health-related quality of life was also significantly higher in the everolimus and exemestane arm compared to the exemestane plus placebo arm. The recently completed BOLERO-3 study showed that mTOR inhibition in combination with trastuzumab plus vinorelbine treatment significantly improved PFS compared to trastuzumab plus vinorelbine alone in trastuzumab-resistant MBC patients.Recent trials have shown that everolimus has produced promising anti-tumor activity in combination with trastuzumab in HER2-positive metastatic breast cancer and in combination with exemestane in patients with hormone-receptor-positive metastatic breast cancer who had recurrence or progression while receiving a nonsteroidal aromatase inhibitor. Results of ongoing studies with everolimus show evidence that using everolimus in earlier stages of the disease, namely in the adjuvant and neoadjuvant settings, could be benefical.

Subcutaneous central venous port catheters (SCVPC) are of great importance in the treatment of patients with malignancies since they provide secure vascular access. Our aim was to assess the impact of long-term catheter care frequency on the frequency of port-related complications.Two hundred and seven patients who had not been on active chemotherapy through their SCVPC for at least 3 months were enrolled into the study. Those who received catheter care every 3 months or more frequently were assigned to the frequent care group, and the others to the infrequent care group. The patients were examined for port-related complications and thrombosis including port occlusion. Routinely in our clinic, catheter care was done by using 300 IU of heparin.According to the frequency of SCVPC care, 49 (23.7 %) patients were in the frequent care group and 158 (76.3 %) were in the infrequent care group. Median follow-up of all patients was 671 days (range 133-1712). Median frequency of port care in the frequent care group was 90 days (range 30-90), but 441.5 days in the infrequent care group (range 91-1630). None of the patients experienced port-related severe complications during the follow-up time. None of them presented with port occlusion. When the groups were analysed for thrombus (symptomatic and asymptomatic), there was no statistically significant difference (6.4 vs 13.8 %, p = 0.17). Those patients who had received more than first-line chemotherapy were found to have more thrombi than the patients who were treated with only one type of chemotherapy protocol (28.6 vs 10.2 %, p = 0.01), and the patients who had metastatic disease at the last control were found out to have thrombi more frequently than the non-metastatic patients (24.3 vs 9.3 %) (p = 0.01).In the present study, there was no difference in port-related severe complications between frequent and infrequent care groups during follow-up. However, the rate of thrombosis was slightly higher in the infrequent port care group.

Background: For early detection of renal damage during the usage of cisplatin based chemotherapy, changes in renal function should be monitored carefully. In recent years, neutrophil gelatinase-associated lipocalin, a small polypeptide molecule, has shown promise as a marker of acute renal failure. The aim of this present study was to assess possible risk prediction of cisplatin-induced nephrotoxicity using serum NGAL. Materials and Methods: A total of 34 consecutive patients with documented serum creatinine at least 24 hours before every cycle of cisplatin-based chemotherapy were included in the study. Demographic and medical data including age, performance status, tumor characteristics and comorbid diseases were collected from medical charts. Renal function was evaluated at least 48 hours before the treatment and at the end of the treatment based on the Modification of Diet in Renal Disease (MDRD) formula. Before and after cisplatin infusion serum NGAL levels were measured for the first and 3rd cycles of chemotherapy. Results: The median age of the study population was 54 (32-70) years. Fifteen patients (41.1%) were treated on an adjuvant basis, whereas 19 patients (58.9%) were treated for metastatic disease. There was no correlation of serum NGAL levels with serum creatinine (r=0.20, p=0.26) and MDRD (r=-0.12, p=0.50) and creatinine clearance-Cockcroft-Gault (r=-0.22, p=0.22) after cisplatin infusion at the end of the 3rd cycle of chemotherapy. Conclusions: In our study, serum NGAL levels were not correlated with the cisplatin induced nephrotoxicity. Further prospective studies are needed to conclude that serum NGAL level is not a good surrogate marker to predict early cisplatin induced nephrotoxicity.

Eribulin is a non-taxane microtubule inhibitor, which can be used after anthracycline and taxane treatment in patients with metastatic breast cancer (MBC). The purpose of this study was to investigate the efficacy and safety of eribulin monotherapy in heavily pretreated MBC patients.In this single-center trial, a total of 66 MBC patients who received eribulin monotherapy in Hacettepe University Cancer Institute between 2013 and 2015 were retrospectively analyzed. Kaplan-Meier survival analysis was carried out for progression free survival (PFS) and for overall survival (OS). Two-sided p values0.05 were considered as statistically significant.Sixty-six patients who received at least one cycle of eribulin were registered. Most patients were heavily pretreated with a median of 4 (range 2-7) previous chemotherapy lines prior to eribulin. Median patient age was 50 years (range 28-67). Most patients were treated with eribulin at 4th or 5th line (33.3 and 27.3%, respectively). Brain metastases were present in 19 (28.8%) patients at the time of initial eribulin administration. Median PFS was 5 (95% CI 4.1-5.8) and median OS was 8 (95% CI 6-9.9) months. Fifteen patients (22.7%) responded to treatment with partial remission (PR) and 36 (54%) had stable disease (SD). No hypersensitivity reactions and no toxic deaths were observed. Three (5%) patients experienced grade 4 neurotoxicity. Fourteen (21.5%) patients developed grade 3-4 neutropenia.Eribulin monotherapy is an effective and safe regimen for MBC patients. Its low toxicity profile compared to other intravenous cytotoxic agents and the ease in its intravenous administration make this agent a preferable option for both physicians and patients.

Obesity has been confirmed to be an adverse prognostic factor in patients who were treated with aromatase inhibitors; however, such relationship has never been thoroughly investigated in patients treated with tamoxifen. The purpose of this study was to examine the effect of body mass index (BMI) on the efficacy of adjuvant tamoxifen in premenopausal patients with hormone receptor-positive breast cancer.Newly diagnosed premenopausal and non-metastatic hormone receptor-positive breast cancer patients were enrolled in the study. Patients with BMI ranging between 18.5 and 24.9 kg/m(2) were considered as normal weight patients (Arm A, n = 408), and/patients with a BMI ≥ 25 kg/m(2) were considered as overweight and obese patients (Arm B, n = 418).In both normal weight and overweight patients, the baseline clinicopathologic properties and the treatment history with radiotherapy and chemotherapy were similar and no statistical significant difference could be detected. Tamoxifen in combination with luteinizing hormone-releasing hormone (LHRH) agonist was used in 33% (136/408) of the patients in Arm A and in 22% (91/418) of patients in Arm B (p0.001). Three-year disease free survival (DFS) rates were 89% and 87% in arm A and arm B, respectively (p=0.39). Three-year overall survival (OS) rates were 99% in arm A and 94% in arm B which appeared to be of significance (p=0.028). In univariate analysis no statistical significant effect of LHRH agonist usage on DFS (p=0.58) and OS (p=0.96) was found.Although BMI had no negative effect on recurrence risk, poor OS was observed in overweight and obese premenopausal breast cancer patients with hormone-receptor positive tumors who were treated with tamoxifen.

Background: Increased adiposity may trigger signalling pathways that induce aromatase expression. As aromatase inhibitors exert their effects by blocking the aromatase enzyme, higher body mass index (BMI) can reduce the effect of aromatase inhibitors. Thus, we aimed to investigate retrospectively the effect of BMI on the efficacy of aromatase inhibitors in hormone receptor-positive postmenopausal patients with breast cancer. Methods: Newly diagnosed hormone receptor-positive breast cancer patients who were postmenopausal and non-metastatic were enrolled to the study. Patients with BMI ranging between 18.5 and 24.9 kg m−2 were considered as normal weight patients (Arm A, n=102), and patients with a BMI ranging ⩾25 kg m−2 were grouped as overweight and obese patients (Arm B, n=399). Results: In both normal weight and overweight patients, the baseline clinico-pathologic properties and the treatment history with radiotherapy and chemotherapy were similar, and with no statistically significant difference. In normal weight patients disease-free survival (DFS) rate was 93.7% and 77.6%, whereas in overweight and obese patients DFS rate was 96.8% and 85.5% in the first and third years, respectively, (P=0.08). Three year survival rate in Arm A patients was 98.3%, whereas in Arm B was 98.0% (P=0.57). When anastrozole was compared with letrozole in the subgroup analysis no difference with regard to DFS and overall survival was detected. Conclusion: These results, contradictory to the prior results, show that BMI has no worse effect on outcomes of aromatase inhibitors in postmenopausal hormone receptor-positive breast cancer patients. In the subgroup analysis, letrozole and anastrozole had similar survival outcomes.

Lack of response in some patients and relapse during the course of therapy in the treatment of HER2-positive early breast cancer and metastatic breast cancer continue to challenge researchers and clinicians towards a better understanding of the fundamental mechanisms of trastuzumab action and new therapies for HER2. The aim of this review is to discuss current and future treatment options with pertuzumab in the light of new insights into HER2-positive breast cancer.Pertuzumab showed positive results in clinical studies and agents in routine clinical usage are updated. The PubMed database, ASCO and San Antonio Breast Cancer Symposium Meeting abstracts were searched up to June 2012 by using the terms 'pertuzumab' and 'anti-HER2 treatment'; papers which were considered relevant for the aim of this review were selected by the authors.The presented trials of phase II and phase III randomized trials of CLEOPATRA, NEOSPHERE and TRYPHAENA have showed pertuzumab action to be complementary to trastuzumab without increasing adverse events. Adding pertuzumab to trastuzumab in the first line of HER2-positive metastatic breast cancer and in the neoadjuvant treatment of locally advanced HER2-positive breast cancer is usually well tolerated. The evaluation of health-related quality of life showed that combining pertuzumab with docetaxel and trastuzumab compared to placebo have no detrimental effect with adding pertuzumab.Pertuzumab is the first HER dimerization inhibitor with a mechanism of action complementary to trastuzumab. Studies with anti-HER2 combination treatments indicate that the use of more than one HER2-targeted therapy was superior to one of these agents alone. Pertuzumab has produced impressive anti-tumor activity in combination with trastuzumab. There are ongoing studies with pertuzumab with an increasing tendency towards moving the study of these agents to earlier stages of the disease, namely in the adjuvant and neoadjuvant setting.

Bisphosphonates are the most commonly used agents in the treatment of osteoporosis, and bisphosphonate therapy reduces the risk of skeletally related complications in patients with bone metastases due to malignancy. However, the effect of oral alendronate treatment on clinical and pathological properties of breast cancer has not been reported. Thus, we aimed to investigate retrospectively the demographic and clinico-pathological characteristics of new diagnosis of breast cancer patients with oral alendronate users for longer than 1 year, compared with non-users. Newly diagnosed breast cancer patients from 1998 to 2010 in our clinic were retrospectively analyzed. Patient’s demographics, including survival data and tumor characteristics, were obtained from medical charts. Breast cancer patients who were taking oral alendronate more than 12 months at the time of breast cancer diagnosis were enrolled as an alendronate users (n = 44), where the patients matched with the same age who were not taking oral alendronate were included as a control group (n = 444). A total of 488 patients were included in this study. Forty-four patients received an oral alendronate treatment more than 1 year, and 444 patients were considered as non-users. Median age of both alendronate users and non-users was 57 (33–89). Lower incidence of histological grade III, T3–T4 tumor, and node positivity was seen in alendronate users but not statistically significant. A similar trend for lower incidence of triple negative and higher incidence ER (P = 0.13), progesterone receptor (P = 0.12), and HER2 positivity (P = 0.21) was also seen in alendronate users but not statistically significant. Estimated median disease-free survival was 150 months in alendronate users where as 70 months in non-users (P = 0.015). Five-year survival rate in alendronate users was 97.4 %, whereas in non-users was 89.8 % (P = 0.13). The use of oral alendronate for longer than 1 year at the time of breast cancer diagnosis was associated with better clinico-pathological properties and significantly improved disease-free survival in breast cancer patients.

10.2217/FON.15.6 © 2015 Future Medicine Ltd Antihormonal treatment with aromatase inhibitors or tamoxifen are the corner stone treatment options in the adjuvant treatment of hormone receptor-positive breast cancer. In last decade, resulted randomized trials showed that aromatase inhibitors provide more benefit than tamoxifen in hormone receptor-positive postmenopausal breast cancer [1]. Due to the significant diseasefree survival (DFS) and lower recurrences benefit with both upfront aromatase inhibitors for 5 years or sequential therapy with tamoxifen for 2–3 years followed by aromatase inhibitors in early breast cancer, aromatase inhibitors have been accepted as first line endocrine treatment in hormone receptor-positive postmenopausal breast cancer [2]. Obesity and overweight patients have independent risk factor for the development of breast cancer and the outcome of breast cancer was significantly poor in obese patients compared with nonobese patients especially in postmenopausal women [3,4]. Overweight or obese postmenopausal women exhibit a threefold increased risk for developing breast cancer compared with normal weight postmenopausal women [5,6]. Weight gain after diagnosis of breast cancer is also associated with decreased survival and less favorable clinical characteristics such as greater tumor burden, higher grade and poorer prognosis [4,7]. Obesity has been accepted the source of abnormal expression of aromatase enzyme in the breast that leads to increase local estrogen production and predisposition to developing breast cancer and the risk of recurrence has been increased significantly compared with nonobese patients especially in postmenopausal breast cancer patients [8]. In contrast to postmenopausal patients, an increased BMI is associated with a lower risk of breast cancer in premenopausal women and in the pooled analysis of seven prospective cohort studies that comprise 337,819 women and 4385 invasive breast cancer patients showed that BMI ≥31 kg/m were 46% less likely to develop breast cancer than those with a BMI