Adrenocortical Cancer in the Real World: A Comprehensive Analysis of Clinical Features and Management from the Turkish Oncology Group (TOG).

INTRODUCTION: Adrenocortical carcinoma (ACC) is a rare yet highly malignant tumor associated with significant morbidity and mortality. This study aims to delineate the clinical features, survival patterns, and treatment modalities of ACC, providing insights into the disease's prognosis. MATERIALS AND METHODS: A retrospective analysis of 157 ACC patients was performed to assess treatment methodologies, demographic patterns, pathological and clinical attributes, and laboratory results. The data were extracted from the hospital's database. Survival analyses were conducted using the Kaplan-Meier method, with univariate and multivariate analyses being performed through the log-rank test and Cox regression analyses. RESULTS: The median age was 45, and 89.4% had symptoms at the time of diagnosis. The median tumor size was 12 cm. A total of 117 (79.6%) patients underwent surgery. A positive surgical border was detected in 26 (24.1%) patients. Adjuvant therapy was administered to 44.4% of patients. The median overall survival for the entire cohort was 44.3 months. Median OS was found to be 87.3 months (95% confidence interval [CI] 74.4-100.2) in stage 2, 25.8 (95% CI 6.5-45.1) months in stage 3, and 13.3 (95% CI 7.0-19.6) months in stage 4 disease. Cox regression analysis identified age, Ki67 value, Eastern Cooperative Oncology Group performance status, and hormonal activity as significant factors associated with survival in patients with nonmetastatic disease. In metastatic disease, only patients who underwent surgery exhibited significantly improved overall survival in univariate analyses. CONCLUSION: ACC is an uncommon tumor with a generally poor prognosis. Understanding the defining prognostic factors in both localized and metastatic diseases is vital. This study underscores age, Ki67 value, Eastern Cooperative Oncology Group performance status, and hormonal activity as key prognostic determinants for localized disease, offering critical insights into the complexities of ACC management and potential avenues for targeted therapeutic interventions.

The efficacy of palbociclib and ribociclib in the first-line treatment of metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer in male patients: a Turkish oncology group (TOG) study.

INTRODUCTION: Male breast cancer, comprising approximately 1% of all breast cancer cases, often leads to the exclusion of male patients as a criterion in clinical trials. While the efficacy of Cyclin-dependent kinases 4 and 6 (CDK 4/6) inhibitors has been established in metastatic hormone receptor-positive (HR +) and human epidermal growth factor receptor 2-negative (HER2 -) breast cancer in women, limited data exist on their effectiveness in male patients. We aimed to evaluate the efficacy and safety of palbociclib or ribociclib in male patients with breast cancer. METHODS: This study is a multicenter, retrospective study. We included male patients with HR + and HER2-metastatic breast cancer who received palbociclib or ribociclib as first-line treatment. Our primary endpoints were progression-free survival (PFS), overall response rates (ORR), and drug-related adverse effects. RESULTS: A total of 46 male patients from 27 institutions were enrolled. The median age at initiation of CDK 4/6 inhibitors was 63.64 ± 13.69 years, with a median follow-up of 21.33 (95% CI 14.92-27.74) months. The ORR were 84% for palbociclib and 76.2% for ribociclib. The mPFS for the entire cohort was 28.06 months (95% CI 18.70-37.42). No significant difference in PFS was observed between palbociclib and ribociclib (mPFS: 24.46 months (95% CI 11.51-37.42) vs 28.33 months (95% CI 14.77-41.88), respectively, p = 0.211). No new adverse events were reported. DISCUSSION: This study demonstrates that palbociclib and ribociclib are effective and safe options for first-line treatment in male patients with HR + /HER2 - metastatic breast cancer. However, further prospective studies are warranted to establish their efficacy in this population.

Is there any prognostic significance in pleural involvement and/or effusion in patients with ALK-positive NSCLC?

PURPOSE: Anaplastic lymphoma kinase (ALK) mutations occurs in approximately 3-5% of patients with non-small cell lung cancer (NSCLC). Pleural involvement/effusion is common in ALK-positive patients with NSCLC at baseline. The aim of the study was to evaluate the characteristics of ALK-positive patients who have Ple-I/E. METHODS: In this multicenter study, patients with ALK-positive NSCLC who have Ple-I/E were retrospectively analyzed. Clinical and demographic characteristics of the disease, response rates, median progression-free survival (PFS), and overall survival (OS) were evaluated in 362 ALK-positive patients with NSCLC. RESULTS: Of the patients, 198 (54.7%) were male. The median age at the time of diagnosis was 54 (range 21-85) years. All patients' histology was adenocarcinoma (100%). At baseline, 57 (15.7%) patients had Ple-I/E. There was no association between Ple-I/E and gender, lung metastasis, or distant lymphadenopathy (LAP) metastasis. The frequencies of liver, brain, and bone metastases were significantly higher in ALK-positive patients without Ple-I/E compared to those with Ple-I/E (respectively 18.2% vs 4.8%, p = 0.008; 19.1% vs 4.8%, p = 0.001; 20.6% vs 8.9%, p = 0.002). The median PFS was longer in ALK-positive patients who had Ple-I/E (18.7 vs 10.6 months, p = 0.017). Similarly, the median OS was longer in ALK-positive patients who had Ple-I/E (44.6 vs 22.6 months, p = 0.051). CONCLUSION: Brain, liver, and bone metastases were lower in ALK-positive patients with Ple-I/E. Patients presented with Ple-I/E were prone to have better PFS and OS.

Impact of adding pertuzumab to trastuzumab plus chemotherapy in neoadjuvant treatment of HER2 positive breast cancer patients: a multicenter real-life HER2PATH study.

AIM: To investigate the pathological complete response (pCR) achieved after neoadjuvant therapy with versus without adding pertuzumab (P) to trastuzumab (H) plus neoadjuvant chemotherapy (NCT) in HER2+ breast cancer (BC) patients in a real-life setting. METHODS: A total of 1528 female HER2+ BC patients who received NCT plus H with or without P were included in this retrospective real-life study. Primary endpoint was pCR rate (ypT0/Tis ypN0). Clinicopathological characteristics, event-free survival (EFS) time, and relapse rates were evaluated with respect to HER2 blockade (NCT-H vs. NCT-HP) and pCR. RESULTS: Overall, 62.2% of patients received NCT-H and 37.8% received NCT-HP. NCT-HP was associated with a significantly higher pCR rate (66.4 vs. 56.8%, p < 0.001) and lower relapse (4.5 vs. 12.2%, p < 0.001) in comparison to NCT-H. Patients with pCR had a significantly lower relapse (5.6 vs. 14.9%, p < 0.001) and longer EFS time (mean(SE) 111.2(1.9) vs. 93.9(2.7) months, p < 0.001) compared to patients with non-pCR. Patients in the NCT-HP group were more likely to receive docetaxel (75.0 vs. 40.6%, p < 0.001), while those with pCR were more likely to receive paclitaxel (50.2 vs. 40.7%, p < 0.001) and NCT-HP (41.5 vs. 32.1%, p < 0.001). Hormone receptor status and breast conservation rates were similar in NCT-HP vs. NCT-H groups and in patients with vs. without pCR. Invasive ductal carcinoma (OR, 2.669, 95% CI 1.596 to 4.464, p < 0.001), lower histological grade of the tumor (OR, 4.052, 95% CI 2.446 to 6.713, p < 0.001 for grade 2 and OR, 3.496, 95% CI 2.020 to 6.053, p < 0.001 for grade 3), lower T stage (OR, 1.959, 95% CI 1.411 to 2.720, p < 0.001) and paclitaxel (vs. docetaxel, OR, 1.571, 95% CI 1.127 to 2.190, p = 0.008) significantly predicted the pCR. CONCLUSIONS: This real-life study indicates that adding P to NCT-H enables higher pCR than NCT-H in HER2+ BC, while pCR was associated with lower relapse and better EFS time.

Demographic and Clinical Features of Patients with Metastatic Breast Cancer: A Retrospective Multicenter Registry Study of the Turkish Oncology Group.

This multicenter registry study aims to analyze time-related changes in the treatment patterns and outcome of patients with metastatic breast cancer (MBC) over a ten-year period. Correlations between demographic, prognostic variables and survival outcomes were carried out in database aggregates consisting of cohorts based on disease presentation (recurrent vs. de novo) and the diagnosis date of MBC (Cohort I: patient diagnosed between January 2010 and December 2014; and Cohort II: between January 2015 and December 2019). Out of 1382 patients analyzed, 52.3% patients had recurrent disease, with an increased frequency over time (47.9% in Cohort I vs. 56.1% in Cohort II, p < 0.001). In recurrent patients, 38.4% (n = 277) relapsed within two years from initial diagnosis, among which triple-negative BC (TNBC) was the most frequent (51.7%). Median overall survival (OS) was 51.0 (48.0-55.0) months for all patients, which was similar across both cohorts. HER2+ subtype had the highest OS among subgroups (HER2+ vs. HR+ vs. TNBC; 57 vs. 52 vs. 27 months, p < 0.001), and the dnMBC group showed a better outcome than recMBC (53 vs. 47 months, p = 0.013). Despite the lack of CDK inhibitors, luminal A patients receiving endocrine therapy had a favorable outcome (70 months), constituting an appealing approach with limited resources. The only survival improvement during the timeframe was observed in HER2+ dnMBC patients (3-year OS Cohort I: 62% vs. Cohort II: 84.7%, p = 0.009). The incorporation of targeted agents within standard treatment has improved the outcome in HER2+ MBC patients over time. Nevertheless, despite advances in early diagnosis and treatment, the prognosis of patients with TNBC remains poor, highlighting the need for more effective treatment options.

Evaluation of Treatment Efficacy of Tyrosine Kinase Inhibitors in Rare Single EGFR Exon 21 L861Q Mutation: Single Center Experience.

OBJECTIVE: Epidermal growth factor receptor mutations are the second most common oncogenic driver event in non-small cell lung cancer. We aimed to compare the first generation erlotinib treatment with the second generation afatinib treatment in patients with non- small cell lung cancer with epidermal growth factor receptor exon 21 L861Q mutation. MATERIAL AND METHODS: Progression-free survival and overall survival of 30 non-small cell lung cancer patients treated with erlo- tinib or afatinib due to single epidermal growth factor receptor L861Q positivity were compared retrospectively. The number of patients included in the first, second, and third treatment line was 15 (50.0%), 11 (36.7%), and 4 (13.3%), respectively. RESULTS: There were 23 patients in the erlotinib arm and 7 patients in the afatinib arm. Median progression-free survival was 12.8 months in the erlotinib group and 9.3 months in the afatinib group. Median overall survival in erlotinib and afatinib groups was 77.9 months and 30.3 months, respectively. No statistically significant difference was found in the comparison of these survival times. CONCLUSION: Survival times of erlotinib and afatinib treatment are similar in patients with a single epidermal growth factor receptor L861Q mutation. In patients receiving tyrosine kinase inhibitors treatment, the female gender has a positive effect on progression-free survival, and being a non-smoker has a positive effect on overall survival. In patients with rare mutation exon 21 L861Q positivity, both first-generation and second-generation tyrosine kinase inhibitors should be considered.

The effectiveness and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early-stage human epidermal growth factor receptor 2-positive breast cancer: Turkish Oncology Group study.

In our study, we aimed to evaluate the pathological response rates and side effect profile of adding pertuzumab to the treatment of HER2+ locally advanced, inflammatory, or early-stage breast cancer. This study was conducted by the Turkish Oncology Group (TOG) with data collected from 32 centers. Our study was multicentric, and a total of 364 patients were included. The median age of the patients was 49 years (18-85 years). Two hundred fifteen (60%) of the cases were hormone receptor/HER2+ positive(ER+ or PR+, or both), and 149 (40%) of them were HER2-rich (ER and PR negative). The number of complete responses was 124 (54%) in the docetaxel+trastuzumab+pertuzumab arm and 102 (45%) in the paclitaxel+trastuzumab+pertuzumab arm, and there was no difference between the groups in terms of complete response. In 226 (62%) patients with complete response, a significant correlation was found with DCIS, tumor focality, removed lymph node, and ER status P < 0.05. Anemia, nausea, vomiting, myalgia, alopecia, and mucosal inflammation were significantly higher in the docetaxel arm, P < 0.05. In our study, no statistical difference was found between the before-after echocardiography values. DCIS positivity in biopsy before neoadjuvant chemotherapy, tumor focality; the number of lymph nodes removed and ER status were found to be associated with pCR. In conclusion, we think that studies evaluating pCR-related clinicopathological variables and radiological imaging features will play a critical role in the development of nonsurgical treatment approaches.

PDL-1 Expression and Survival in Metastatic Non-small Cell Lung Cancer Patients Who Received Chemotherapy as First-Line Treatment.

OBJECTIVE: To show the effect of programmed cell death protein-1ligand (PDL-1) level on survival times in patients with metastatic non-small cell lung cancer (mNSCLC) receiving chemotherapy, to determine the relationship between PDL-1 level, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). MATERIAL AND METHODS: The data of 158 patients who received chemotherapy for mNSCLC were evaluated retrospectively. Clinical and demographic data, PDL-1 expression levels and follow-up periods of the patients were recorded. The patients were divided into 2 groups according to PDL-1 levels. RESULTS: In all patients, progression free survival (PFS) was 5.6 months and overall survival (OS) was 18.8 months. Patients with low PDL-1 had a longer PFS than patients with high PDL-1 (p:0.038). In the gemcitabine and taxane groups, patients with low PDL-1 had a longer PFS than patients with high PDL-1 (p:0.047). There was a significant correlation between NLR and PDL-1 levels. In the groups with high PDL-1, patients with low NLR levels had higher OS than patients with high NLR level (p:0.043). Also, there was a significant difference between the OS patients with low and high PLR levels (p:0.520). CONCLUSION: In patients with mNSCLC whose PDL-1 levels and NLR levels are low, immunogenic chemotherapies such as gemcitabine and taxane can be tried as an alternative treatment.

Predictive role of neutropenia under crizotinib treatment in ALK-rearranged nonsmall cell lung cancer patients: A single-institution retrospective analysis.

Background: Anaplastic lymphoma kinase (ALK)-rearranged nonsmall cell lung cancer (NSCLC) represents a molecular subgroup with high sensitivity to ALK inhibitors. Tyrosine kinase inhibitor crizotinib, an anticancer drug acting as an ALK inhibitor, has shown remarkable response in ALK-positive NSCLC. The aim of our study is to explore the adverse events (AEs) of patients on crizotinib therapy and analyze the predictability of AEs for better survival or response on NSCLC patients. Methods: The medical records of our ALK-positive metastatic NSCLC patients who applied between years 2013 and 2018 had been reviewed retrospectively. ALK positivity of all patients had been detected by fluorescence in situ hybridization and no other driver mutations were present. Patient demographics, performance status, smoking history, previous treatments, metastatic sites, and AEs were recorded for further analyses. Results: Thirty-six ALK-positive metastatic NSCLC patients were included in the study. Median follow-up was 30.1 months. Median progression-free survival (PFS) for patients who developed hepatic, cardiac, or endocrine toxicities was similar when compared to patients who did not develop. Although there was a numeric median PFS difference between patients who did develop visual disorders (18.4 months) and did not develop visual disorders (15.5 month), this was not regarded as statistically significant. However, median PFS of the patients who developed neutropenia upon crizotinib treatment (31.9 months) was found to be more favorable than the patients with normal neutrophil counts (12.8 months) (P = 0.026). Conclusion: Neutropenia under crizotinib treatment was found to be associated with improved PFS suggesting that neutropenia might be an important determinant in treatment and survival strategies.

Efficacy and Safety of Trastuzumab Emtansine in Her2 Positive Metastatic Breast Cancer: Real-World Experience.

AIM: The aim of this study is to evaluate the efficacy and toxicity of trastuzumab emtansine (T-DM1) in cases with metastatic breast cancer (mBC) in different lines of treatment. METHOD: Retrospective analysis of T-DM1 results of human epidermal growth factor receptor 2 (Her2) positive 414 cases with mBC from 31 centers in Turkey. FINDINGS: Except 2, all of the cases were female with a median age of 47. T-DM1 had been used as second-line therapy in 37.7% of the cases and the median number of T-DM1 cycles was 9. Progression-free survival (PFS) and overall survival (OS) times were different according to the line of treatment. The median OS was found as 43, 41, 46, 23 and 17 months for 1st, 2nd, 3rd, 4th and 5th line, respectively (p = 0.032) while the median PFS was found as 37, 12, 8, 8 and 8 months, respectively (p = 0.0001). Treatment was well tolerated by the patients. The most common grade 3-4 adverse effects were thrombocytopenia (2.7%) and increased serum gamma-glutamyl transferase (2%). DISCUSSION: The best of our knowledge this is the largest real-life experience about the safety and efficacy of T-DM1 use in cases with mBC after progression of Her2 targeted treatment. This study suggests and supports that T-DM1 is more effective in earlier lines of treatment and is a reliable option for mBC.

Prognostic factors in patients with metastatic urothelial carcinoma who have treated with Atezolizumab.

BACKGROUND: Atezolizumab (ATZ) has demonstrated antitumor activity and manageable safety in previous studies of patients with metastatic platinum-resistant urothelial carcinoma. However, the response rate of Atezolizumab was modest. In the current study, we evaluated the pretreatment prognostic factors for overall survival in patients with metastatic urothelial carcinoma who have progressed after first-line chemotherapy in the Expanded-Access Program of Atezolizumab. PATIENTS AND METHODS: In this study, we present a retrospective analysis of 113 patients with urothelial cancer treated with ATZ after progression on first-line chemotherapy. Data of the patients was obtained from patient files and hospital records. Eligible patients included metastatic urothelial carcinoma patients treated with at least one course of ATZ. Univariate analysis was used to identify clinical and laboratory factors that significantly impact OS. Variables were retained for multivariate analysis if they had a statistical relationship with OS (p < 0.1), and then included a final model of p < 0.05. RESULTS: The median follow-up duration was 23.5 months. Of the patients, 98 (86.7%) were male and 13.3% were female. The median age was 65 years of age (37-86). In univariate analysis, primary tumor location in the upper tract, increasing absolute neutrophil count (ANC), increasing absolute lymphocyte count, neutrophil-to-lymphocyte ratio (NLR) > 3, liver metastases, baseline creatinine clearance less (GFR) than 60 ml/min, Eastern Cooperative Oncology Group (ECOG) performance status (1 ≥), and hemoglobin levels below 10 mg/dl were all the significantly associated with OS. Three of the five adverse prognostic factors according to the Bellmunt criteria were independent of short survival: liver metastases HR 3.105; 95% CI 1.673-5.761; p < (0.001), ECOG PS (1 ≥) HR 2.184; 95% CI 1.120-4.256; p = 0.022, and Hemoglobin level below 10 mg/dl HR 2.680; 95% CI 1.558-4.608; p < (0.001). In addition, NLR > 3 hazard ratio [HR] 2.092; 95% CI 1.031-4.243; p = 0.041 and GFR less than 60 ml/min HR 1.829; 95% CI 1.1-3.041; p = 0.02, maintained a significant association with OS in multivariate analysis. CONCLUSIONS: This model confirms the Bellmunt model with the addition of NLR > 3 and GFR less than 60 ml/min and can be associated with clinical trials that use immunotherapy in patients with bladder cancer.

Thymoquinone Glucuronide Conjugated Magnetic Nanoparticle for Bimodal Imaging and Treatment of Cancer as a Novel Theranostic Platform.

BACKGROUND: Theranostic oncology combines therapy and diagnosis and is a new field of medicine that specifically targets the disease by using targeted molecules to destroy the cancerous cells without damaging the surrounding healthy tissues. OBJECTIVE: We aimed to develop a tool that exploits enzymatic TQ release from glucuronide (G) for the imaging and treatment of lung cancer. We added magnetic nanoparticles (MNP) to enable magnetic hyperthermia and MRI, as well as 131I to enable SPECT imaging and radionuclide therapy. METHODS: A glucuronide derivative of thymoquinone (TQG) was enzymatically synthesized and conjugated with the synthesized MNP and then radioiodinated with 131I. New Zealand white rabbits were used in SPECT and MRI studies, while tumor modeling studies were performed on 6-7- week-old nude mice utilized with bioluminescence imaging. RESULTS: Fourier-transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR) spectra confirmed the expected structures of TQG. The dimensions of nanoparticles were below 10 nm and they had rather polyhedral shapes. Nanoparticles were radioiodinated with 131I with over 95% yield. In imaging studies, in xenograft models, tumor volume was significantly reduced in TQGMNP-treated mice but not in non-treated mice. Among mice treated intravenously with TQGMNP, xenograft tumor models disappeared after 10 and 15 days, respectively. CONCLUSION: Our findings suggest that TQGMNP in solid, semi-solid and liquid formulations can be developed using different radiolabeling nuclides for applications in multimodality imaging (SPECT and MRI). By altering the characteristics of radionuclides, TQGMNP may ultimately be used not only for diagnosis but also for the treatment of various cancers as an in vitro diagnostic kit for the diagnosis of beta glucuronidase-rich cancers.

Atezolizumab in Patients with Metastatic Urothelial Carcinoma Who Have Progressed After First-line Chemotherapy: Results of Real-life Experiences.

BACKGROUND: Atezolizumab (ATZ) has demonstrated antitumor activity and manageable safety in previous studies in patients with locally advanced or metastatic platinum-resistant urothelial carcinoma. OBJECTIVE: To compare the real-life experience and data of clinical trials on ATZ treatment in metastatic urothelial carcinoma. DESIGN, SETTING, AND PARTICIPANTS: Patients with urothelial cancer treated with ATZ after progression on first-line chemotherapy from an expanded access program were retrospectively studied. Data of patients were obtained from their files and hospital records. Safety was evaluated for patients treated with at least one cycle of ATZ. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was objective response rate (ORR). The secondary endpoints are overall survival (OS), progression-free survival (PFS), duration of response, and safety profile of patients. Kaplan-Meier methods were used to calculate median follow-up and estimate PFS and OS. RESULTS AND LIMITATIONS: Data of 115 enrolled patients were analyzed. Most of the patients (92.3%, n = 106) had received chemotherapy regimen only once prior to ATZ. The median follow-up duration was 23.5 mo. The complete response rate, partial response rate, and ORR were 8.7% (n = 10), 20.0% (n = 23), and 28.7% (n = 33), respectively. The median duration of response was 20.4 mo (95% confidence interval [CI], 6.47-28.8). Of the 33 patients who responded to treatment, 60% (n = 20) had an ongoing response at the time of the analysis. PFS and OS with ATZ were 3.8 mo (95% CI, 2.25-5.49) and 9.8 mo (95% CI, 6.7-12.9), respectively. All-cause and any-grade adverse events were observed in 113 (98%) patients. Of the patients, 64% experienced a treatment-related adverse event of any grade and 24 (21.2%) had a grade 3-4 treatment-related adverse event. Limitations of the study included its retrospective design, and determination of treatment response based on clinical notes and local radiographic studies. CONCLUSIONS: In these real-life data, ATZ was effective and well tolerated in patients with metastatic urothelial carcinoma who have progressed with platinum-based first-line chemotherapy. ATZ is an effective and tolerable treatment for patients with locally advanced or metastatic platinum-resistant urothelial carcinoma in our study, similar to previously reported trials. PATIENT SUMMARY: Atezolizumab is effective and well-tolerated in patients with metastatic urothelial cancer who progressed with first-line chemotherapy, consistent with the outcomes of the previous clinical trials in this setting.

The effectiveness of cetuximab and panitumumab when combined with FOLFIRI in second-line treatment of KRAS wild type metastatic colorectal cancers. Single centre experience.

Panitumumab and cetuximab are monoclonal antibodies known to be effective in metastatic colorectal cancer (mCRC). Although the survival benefits when combined with chemotherapy have been determined, there are no studies comparing the two agents with chemotherapy in the second-line treatment. In this study, we aimed to compare the efficacy of cetuximab vs panitumumab in patients who previously received chemotherapy. Who progressed after first-line treatment for K-ras wild type mCRC were analyzed. The efficacy of cetuximab vs panitumumab on overall survival (OS) and progression-free survival (PFS) when combined with FOLFIRI regimen was compared retrospectively. Median PFS was 6.9 months in the cetuximab group and 4.7 months in the panitumumab group. Median OS cetuximab and panitumumab groups were 18.4 and 12.2 months, respectively. In the second-line treatment of K-ras wild type mCRC, both PFS and OS were found to be longer in patients receiving cetuximab than in patients receiving panitumumab, but no statistically significant difference was found.

Neurofibromin Is an Estrogen Receptor-α Transcriptional Co-repressor in Breast Cancer.

We report that neurofibromin, a tumor suppressor and Ras-GAP (GTPase-activating protein), is also an estrogen receptor-α (ER) transcriptional co-repressor through leucine/isoleucine-rich motifs that are functionally independent of GAP activity. GAP activity, in turn, does not affect ER binding. Consequently, neurofibromin depletion causes estradiol hypersensitivity and tamoxifen agonism, explaining the poor prognosis associated with neurofibromin loss in endocrine therapy-treated ER+ breast cancer. Neurofibromin-deficient ER+ breast cancer cells initially retain sensitivity to selective ER degraders (SERDs). However, Ras activation does play a role in acquired SERD resistance, which can be reversed upon MEK inhibitor addition, and SERD/MEK inhibitor combinations induce tumor regression. Thus, neurofibromin is a dual repressor for both Ras and ER signaling, and co-targeting may treat neurofibromin-deficient ER+ breast tumors.

Cost effectiveness of Gene Expression Profiling in Patients with Early-Stage Breast Cancer in a Middle-Income Country, Turkey: Results of a Prospective Multicenter Study.

OBJECTIVE: Breast cancer is a heterogenous disease, and genetic profiling helps to individualize adjuvant treatment. The Oncotype DX is a validated test to predict benefit of adjuvant systemic treatment. The aims of this study are to determine the costs of chemotherapy in government hospitals in Turkey and evaluate the cost-effectiveness of the Oncotype DX from the national insurance perspective. MATERIALS AND METHODS: A Markov model was developed to make long term projections of distant recurrence, survival, quality adjusted life expectancy, and direct costs for patients with ER+, HER2-, node-negative or up to 3 node-positive early stage breast cancer. Turkish decision impact study patient data were captured for model reference. In that study, ten academic centers across Turkey participated in a prospective trial. Of 165 patients with pT1-3, pN0-N1mic, ER-positive, and HER-2 negative tumors, 57% had low recurrence score (RS), 35% had intermediate RS, and 8% had high RS, respectively. The overall rate of change in chemotherapy treatment decisions following Oncotype DX was 33%. RESULTS: The cost of adjuvant chemotherapy in public hospitals was estimated at $3.649, and Oncotype Dx test was $5.141. Based on the cost-effectiveness analysis, Oncotype DX testing was estimated to improve life expectancy (+0.86 years) and quality-adjusted life expectancy (+0.68 QALYs) versus standard care. The incremental cost-effectiveness ratio (ICERs) of Oncotype DX was estimated to be $7207.9 per QALY gained and $5720.6 per LY gained versus current clinical practice. CONCLUSION: As Oncotype DX was found both cost-effective and life-saving from a national perspective, the test should be introduced to standard care in patients with ER+, HER-2 negative early-stage breast cancer in Turkey.

The Impact of Subtype Distribution in Inflammatory Breast Cancer Outcome.

OBJECTIVE: Inflammatory breast cancer (IBC) has an unfavourable prognosis despite the advances made in the treatment of breast cancer. Our study aimed to define immunohistochemistry-based surrogate subtype distribution to determine whether the breast cancer subtype accompanied survival outcome differences in IBC. MATERIALS AND METHODS: Medical records of female breast cancer patients with non-metastatic inflammatory breast cancer admitted to our clinic between March 2000 and December 2015 were retrospectively reviewed. Patient demographics, clinical and pathological feature of the primary tumour, adjuvant treatment options and survival data were analysed. Intrinsic breast cancer subtypes were defined according to ER, PR, HER-2 and ki-67 status. RESULTS: We identified 129 non-metastatic inflammatory breast cancer patients. Median follow-up was 73 months. 10 (7.7%) were luminal A-like, 67 (51.9%) were luminal B-like, 37 (28.6%) were HER-2 positive, and 15 (11.6%) were triple negative (TNBC) by immunohistochemistry. There were no statistically significant differences between subtypes in terms of histological type, grade, tumour size and lymph node status. Median disease-free survival was 47 months (95% confidence interval [CI] 29.2-82.6) and median overall survival was 75 months (95% CI 64.7-90.8). Triple negative breast cancer showed poorer outcome than other subgroups. Presence of TNBC disease was associated with poorer outcome compared to luminal A (HR: 0.19, 95% CI 0.04-0.92, p: 0.039), luminal B (HR: 0.34, 95% CI 0.15-0.74, p: 0.007) and HER-2 positive subgroups (HR: 0.40, 95% CI 0.17-0.94, p:0.037). Luminal A patients had a trend to have a better overall survival which did not reach to a statistical significant difference. CONCLUSION: Our study put forth that IBC have a poor prognosis irrespective of breast cancer surrogate subtype distribution. Luminal A, the most frequent subtype of breast cancer was the least common in our IBC patient group. TNBC had the worst outcome when compared to other breast cancer subtypes.

The Role of Genetic Testing in the Selection of Therapy for Breast Cancer: A Review.

IMPORTANCE: The application of next-generation sequencing (NGS) genomic testing for somatic mutations in breast oncology has been slower than anticipated due to issues with clinical applicability and natural heterogeneity of breast cancer. This review summarizes the state of the field and considers approaches for more effective implementation. OBSERVATIONS: While there is an emerging role for germline genetic testing potentially predicting sensitivity to platinum salts and PARP inhibitors, the data regarding somatic mutation for prediction of drug sensitivity remains controversial. Currently, there are no guidelines or regulatory approvals for genomic somatic tumor mutation testing to direct therapy. However, some small populations show promise, such as those with ERBB2/HER2 mutation who may represent the first population to have a positive drug somatic mutation match. Similarly, those with ESR1 mutation may be the first to emerge for a negative association with the efficacy of aromatase-inhibitor treatment. One of the barriers to progress is the necessary focus on metastatic disease, which is often challenging, expensive, and risky to biopsy. In addition, because of the clonal heterogeneity of advanced disease, a single sample may not contain all the genomic information necessary for treatment. Thus, circulating tumor DNA analysis is perhaps one of the most practical and promising approaches. CONCLUSIONS AND RELEVANCE: Circulating tumor DNA analysis, once sensitive and broad enough, will accelerate progress in the quest to make NGS technologies relevant to breast cancer treatment. A broad and coordinated coalition to systematically connect somatic mutations to clinical and pharmacologic data will be critical for progress. We recommend instituting an open source encyclopedia, which would serve as a reference for NGS sequencing report interpretation and would be available to all clinicians to help direct therapy.

Adjuvant chemotherapy may contribute to an increased risk for metabolic syndrome in patients with breast cancer.

PURPOSE: Cytotoxic treatment may cause weight gain and important alterations in the metabolic status of breast cancer (BC) patients. The aim of this study was to investigate the changes in metabolic and anthropometric parameters of patients with BC who received adjuvant chemotherapy. METHODS: All consecutive women treated with adjuvant TAC (docetaxel 75 mg/m(2), doxorubicine 50 mg/m(2), cyclophosphamide 500 mg/m(2)) chemotherapy for node-positive breast carcinoma at our Institution between 2008 and 2010 were included. RESULTS: Among 104 patients, 84 of them were stage II and 20 of them were stage III. When we compared the measurements between 1(st) and 6(th) adjuvant chemotherapy, we observed statistically significant increases in weight and serum triglyceride levels, and decreases in high density lipoprotein, apolipoprotein A-1, transferrin, albumin and prealbumin levels. An elevation of follicle stimulating hormone, luteinizing hormone together with the decrease of estradiol was detected. Waist-to-hip ratio has also increased significantly. In subgroup analyses, we observed dramatic changes in body mass index in pre-menopausal women whereas no significant change was seen in the post-menopausal group. CONCLUSIONS: Adjuvant chemotherapy may contribute to an increased risk for metabolic syndrome in patients with BC and these changes are more profound in pre-menopausal patients.