Is insulin resistance a predictor for complete response in breast cancer patients who underwent neoadjuvant treatment?

PURPOSE: Neoadjuvant chemotherapy is the standard front-line treatment modality in locally advanced breast cancer. Achieving pathological complete response (pCR) is a significant prognostic factor for prolonged disease-free and overall survival. Insulin resistance is defined as a pathological condition in which insulin effect is impaired in peripheral target tissues such as the skeletal muscle, liver, and adipose tissue. The relationship between breast cancer and insulin resistance is controversial. In this study, our aim is to evaluate the role of insulin resistance, body mass index (BMI), metabolic syndrome, and inflammation markers to predict complete response in breast cancer patients who underwent neoadjuvant treatment. METHODS: Data from 55 locally advanced non-diabetic breast cancer patients, treated with neoadjuvant chemotherapy between 2015 and 2017, were retrospectively evaluated. Homeostatic model assessment, IR = insulin resistance (HOMA-IR) was calculated by using the obtained insulin and fasting blood glucose values before neoadjuvant chemotherapy (fasting insulin × fasting glucose/405). We considered a cut-off of 2.5 for insulin resistance. The systemic inflammatory index (SII), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio (PLR) were calculated. RESULTS: Twenty-five patients had no insulin resistance. The most common pathologic subtype (56%) was hormone receptor (HR) positive and human epidermal growth factor receptor-2 (Her-2)-negative invasive ductal carcinoma. Sixteen (29%) patients had a pathological complete response (pCR). We found that the probability of pCR in patients with insulin resistance was 4.7 times lower than that in patients without insulin resistance [OR: 4.7 (95%CI 1.7-17.2), p = 0.01]. CONCLUSION: Our results revealed that insulin resistance may have a negative effect on pathological complete response (pCR) following neoadjuvant therapy particularly with hormone-positive and Her-2-negative cases of non-diabetic breast cancer.

Changes in 18F-FDG-PET/CT tumor metabolism are not consistent with pathologic complete response in hormone-positive breast cancer.

PURPOSE: Current evaluation of response to neoadjuvant chemotherapy (NAC) shows that it could achieve pathological complete response (pCR). The purpose of this study was to assess the consistency of maximum uptake values (SUVmax) changes and pCR in hormone-positive locally advanced breast cancer (LABC). METHODS: Ninety hormone-positive LABC patients treated at Marmara University Medical Oncology Clinic, Istanbul, Turkey, between 2009 and 2015 were retrospectively studied. All eligible patients (n=5) received NAC (4-8 cycles) and were evaluated for pCR. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18FFDG- PET/CT) scan was performed before and after the completion of NAC. The relative changes of SUVmax both in the primary tumor and the axilla were assessed for consistency with pCR. RESULTS: The patient median age was 46 years (range 26- 76). The patients 13.7% achieved pCR. Values of >50% (n=40) and <50% (n=11) SUVmax changes were not associated with pCR (15% and 18% respectively) (p=1.00). Patients with >75% SUVmax changes could achieve pCR of 20%. Interestingly, most patients with complete metabolic response did not achieve pCR (81%). The difference of the Ki67 levels before and after NAC, tumor localization, HER- 2 positivity, menopausal status, grade of differentiation, lymphovascular and perineural invasion were not associated with pCR. CONCLUSION: SUVmax changes in later cycles of NAC as commonly practised in oncology clinics were not consistent with pCR (p=1.0). Complete metabolic response may not be associated with pCR in hormone-positive LABC. However, almost 80% of patients had >50% decrease in SUVmax and may still have a chance for conservative surgery and less postoperative morbidity. Therefore, 18F-FDG-PET/CT may still have a role to evaluate the tumor response with a need of larger studies and analysis for cost-effectiveness.

Systematic Drug Screening Identifies Tractable Targeted Combination Therapies in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) remains an aggressive disease without effective targeted therapies. In this study, we addressed this challenge by testing 128 FDA-approved or investigational drugs as either single agents or in 768 pairwise drug combinations in TNBC cell lines to identify synergistic combinations tractable to clinical translation. Medium-throughput results were scrutinized and extensively analyzed for sensitivity patterns, synergy, anticancer activity, and were validated in low-throughput experiments. Principal component analysis revealed that a fraction of all upregulated or downregulated genes of a particular targeted pathway could partly explain cell sensitivity toward agents targeting that pathway. Combination therapies deemed immediately tractable to translation included ABT-263/crizotinib, ABT-263/paclitaxel, paclitaxel/JQ1, ABT-263/XL-184, and paclitaxel/nutlin-3, all of which exhibited synergistic antiproliferative and apoptotic activity in multiple TNBC backgrounds. Mechanistic investigations of the ABT-263/crizotinib combination offering a potentially rapid path to clinic demonstrated RTK blockade, inhibition of mitogenic signaling, and proapoptotic signal induction in basal and mesenchymal stem-like TNBC. Our findings provide preclinical proof of concept for several combination treatments of TNBC, which offer near-term prospects for clinical translation. Cancer Res; 77(2); 566-78. ©2016 AACR.

Uptake of exemestane chemoprevention in postmenopausal women at increased risk for breast cancer.

Despite their efficacy, uptake of selective estrogen receptor modulators for breast cancer chemoprevention remains low. Exemestane, an aromatase inhibitor, has recently been identified as a potential chemopreventive option with fewer serious side effects compared with selective estrogen receptor modulators in postmenopausal women. The purpose of this study was to assess the uptake of exemestane in a breast cancer prevention clinic. A retrospective chart review was conducted to capture chemoprevention uptake by postmenopausal women presenting to the Yale Breast Cancer Prevention Clinic between November 2011 and November 2012. Descriptive statistics of the study population have been presented. Statistical analyses were carried out using SAS 9.3 (SAS Institute Inc., Cary, North Carolina, USA) between December 2012 and February 2013. Of 90 postmenopausal women, 56 were eligible for chemoprevention. Their mean age was 56.8 years. Among the women, 39% had osteopenia or osteoporosis. Thirteen women chose to start chemoprevention medication (23%). Although 31% of the chemopreventive medication administered included exemestane, only four of 56 postmenopausal women opted for exemestane (7%). Chemoprevention uptake rates of postmenopausal women in the setting of a breast cancer prevention clinic are higher than that reported in the general population; however, they remain low overall despite the inclusion of exemestane as an option. A significant proportion of postmenopausal women have decreased bone density, which is a potential barrier to exemestane uptake. The results provide practical implications suggesting that exemestane may have limited impact on breast cancer chemoprevention uptake. Further investigations should focus on understanding the factors that influence, predict, and increase chemoprevention uptake.

Prospective assessment of the decision-making impact of the Breast Cancer Index in recommending extended adjuvant endocrine therapy for patients with early-stage ER-positive breast cancer.

Extended adjuvant endocrine therapy (10 vs. 5 years) trials have demonstrated improved outcomes in early-stage estrogen receptor (ER)-positive breast cancer; however, the absolute benefit is modest, and toxicity and tolerability challenges remain. Predictive and prognostic information from genomic analysis may help inform this clinical decision. The purpose of this study was to assess the impact of the Breast Cancer Index (BCI) on physician recommendations for extended endocrine therapy and on patient anxiety and decision conflict. Patients with stage I-III, ER-positive breast cancer who completed at least 3.5 years of adjuvant endocrine therapy were offered participation. Genomic classification with BCI was performed on archived tumor tissues and the results were reported to the treating physician who discussed results with the patient. Patients and physicians completed pre- and post-test questionnaires regarding preferences for extended endocrine therapy. Patients also completed the validated traditional Decisional Conflict Scale (DCS) and State Trait Anxiety Inventory forms (STAI-Y1) pre- and post-test. 96 patients were enrolled at the Yale Cancer Center [median age 60.5 years (range 45-87), 79% postmenopausal, 60% stage I). BCI predicted a low risk of late recurrence in 59% of patients versus intermediate/high in 24 and 17%, respectively. Physician recommendations for extended endocrine therapy changed for 26% of patients after considering BCI results, with a net decrease in recommendations for extended endocrine therapy from 74 to 54%. After testing, fewer patients wanted to continue extended therapy and decision conflict and anxiety also decreased. Mean STAI and DCS scores were 31.3 versus 29.1 (p = 0.031) and 20.9 versus 10.8 (p < 0.001) pre- and post-test, respectively. Incorporation of BCI into risk/benefit discussions regarding extended endocrine therapy resulted in changes in treatment recommendations and improved patient satisfaction.

Multigene prognostic tests in breast cancer: past, present, future.

There is growing consensus that multigene prognostic tests provide useful complementary information to tumor size and grade in estrogen receptor (ER)-positive breast cancers. The tests primarily rely on quantification of ER and proliferation-related genes and combine these into multivariate prediction models. Since ER-negative cancers tend to have higher proliferation rates, the prognostic value of current multigene tests in these cancers is limited. First-generation prognostic signatures (Oncotype DX, MammaPrint, Genomic Grade Index) are substantially more accurate to predict recurrence within the first 5 years than in later years. This has become a limitation with the availability of effective extended adjuvant endocrine therapies. Newer tests (Prosigna, EndoPredict, Breast Cancer Index) appear to possess better prognostic value for late recurrences while also remaining predictive of early relapse. Some clinical prediction problems are more difficult to solve than others: there are no clinically useful prognostic signatures for ER-negative cancers, and drug-specific treatment response predictors also remain elusive. Emerging areas of research involve the development of immune gene signatures that carry modest but significant prognostic value independent of proliferation and ER status and represent candidate predictive markers for immune-targeted therapies. Overall metrics of tumor heterogeneity and genome integrity (for example, homologue recombination deficiency score) are emerging as potential new predictive markers for platinum agents. The recent expansion of high-throughput technology platforms including low-cost sequencing of circulating and tumor-derived DNA and RNA and rapid reliable quantification of microRNA offers new opportunities to build extended prediction models across multiplatform data.

Prognostic factors and adjuvant treatments for surgically treated cancers of the biliary tract: a multicentre study of the Anatolian Society of Medical Oncology (ASMO).

BACKGROUND: Biliary tract cancers are rare, and surgical resection is the standard treatment at early stages. However, reports on the benefits of adjuvant treatment following surgical resection are conflicting. This study aimed to evaluate the factors affecting survival and adjuvant treatments in patients with surgically treated biliary tract cancers. MATERIALS AND METHODS: Patient clinical features, adjuvant treatments, and efficacy and prognostic factor data were evaluated. Survival analyses were performed using SPSS 15.0. RESULTS: The median overall survival was 30.7 months (95% confidence interval [CI], 18.4-42.9 months). Median survival was 19 months (95% CI, 6-33) for patients treated with fluorouracil based chemotherapy and 53 months (95% CI, 33.2-78.8) with gemcitabine based chemotherapy (p=0.033). On univariate analysis, poor prognostic factors for survival were galbladder localization, perineural invasion, hepatic invasion, a lack of adjuvant chemoradiotherapy treatment, and a lack of lymph node dissection. On multivariate analysis, perineural invasion was a poor prognostic factor (p=0.008). CONCLUSIONS: Biliary tract cancers generally have poor prognoses. The main factors affecting survival are tumour localization, perineural invasion, hepatic invasion, adjuvant chemoradiotherapy, and lymph node dissection. Gemcitabine-based adjuvant chemotherapy is more effective than 5-fluorouracil-based chemotherapy.

Treatment and prognostic factors in primary peritoneal carcinoma: a multicenter study of the Anatolian Society of Medical Oncology (ASMO).

BACKGROUND: In this study, we aimed to evaluate the clinicopathological characteristics and prognosis of patients with primary peritoneal carcinoma (PPC), and the effectiveness and toxicity of first-line platinum/taxane combination therapy. PATIENTS AND METHODS: We retrospectively evaluated 79 patients with PPC, who were treated and followed up between December 2001 and August 2012 at 10 medical oncology clinics. RESULTS: All patients were female, with a median age of 63 years (range 34-79 years). Histopathological diagnoses included primary peritoneal serous carcinoma (PPSC) (n = 69) and mixed epithelial carcinoma of the peritoneum (MEC) (n = 10). Patients received first-line treatment with carboplatin/paclitaxel (n = 67) or cisplatin/paclitaxel (n = 12) combination therapy. Overall response rate, median progression-free survival, and median survival time in the paclitaxel/carboplatin group and the paclitaxel/cisplatin group were 74.6 vs. 75%, 15.6 vs. 37.8 months, and 41 vs. 70.3 months, respectively. In multivariate analysis, favorable prognostic factors were: ECOG performance status 0 (p < 0.001) and optimal cytoreduction (p = 0.03). CONCLUSION: PPC is a rare, heterogeneous disease. ECOG performance status and optimal cytoreduction are important prognostic factors regarding survival rates. Platinum/taxane combination therapy is an effective and tolerable regimen in this patient group.

Global gene expression changes induced by prolonged cold ischemic stress and preservation method of breast cancer tissue.

BACKGROUND: Tissue handling can alter global gene expression potentially affecting the analytical performance of genomic signatures, but such effects have not been systematically evaluated. METHODS: Tissue samples from 11 previously untreated breast tumors were minced and aliquots were either snap frozen or placed in RNAlater immediately or after 20, 40, 60, 120 or 180 min at room temperature. RNA was profiled on Affymetrix HG-U133A arrays. We used probe-set-wise hierarchical models to evaluate the effect of preservation method on transcript expression and linear mixed effects models to assess the effect of cold ischemic delay on the expression of individual probe sets. Gene set enrichment analysis identified pathways overrepresented in the affected transcripts. We combined the levels of 41 most sensitive transcripts to develop an index of ischemic stress. RESULTS: Concordance in global gene expression between the baseline and 40 min delay was higher for samples preserved in RNAlater (average concordance correlation coefficient CCC = 0.92 compared to 0.88 for snap frozen). Overall, 481 transcripts (3%) were significantly affected by the preservation method, most of them involved in processes important in cancer. Prolonged cold ischemic delay of up to 3 h induced marginal global gene expression changes (average CCC = 0.90 between baseline and 3 h delay). However 41 transcripts were significantly affected by cold ischemic delay. Among the induced transcripts were stress response genes, apoptotic response genes; among the downregulated were genes involved in metabolism, protein processing and cell cycle regulation. An index combining the expression levels of these genes was proportional to the cold ischemic delay. CONCLUSIONS: Prolonged cold ischemia induces significant transcriptional changes in a small subset of transcripts in the tissue. Furthermore, the expression level of about 3% of the transcripts is affected by the preservation method. These sensitive transcripts should not be included in genomic signatures for more reliable analytical performance.

Salvage treatment experience in advanced synovial sarcoma: a multicenter retrospective analysis of the Anatolian society of medical oncology.

BACKGROUND: We aimed to evaluate prognostic factors and response rates to various treatment approaches to patients with synovial sarcoma in an advanced setting. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 55 patients (18 pts; 32.7% women) diagnosed with synovial sarcomas. Twenty had metastatic disease at the time of diagnosis while the remainder of the study group consisted of patients who developed metastatic or inoperable locally advanced disease during follow up. RESULTS: The median follow up time was 15 months (range: 1-53). Regarding outcomes for the 55 patients, 3 and 5 year overall survival rates were 26% and 14%, respectively. In univariate analyses among demographic factors female gender was associated with a better outcome (p=0.030). Patients with early progressing disease (<2 years) had a worse prognosis when compared to patient group with late relapse, but this difference did not reach statistical significance (p=0.056). According to multivariate Cox regression analysis patients who had undergone metastasectomy had a significant survival advantage (p=0.044). The overall response rate to different salvage chemotherapy regimens given as second line treatment was around 42.9-53.9% for all regimes. There were no statistically significant differences between chemotherapy regimens given in either second or third line settings in terms of overall survival. CONCLUSIONS: We observed no major differences in terms of response rate and survival between different salvage chemotherapy regimens. Although metastatic disease still carries a poor prognosis, metastasectomy was found to be associated with improved survival.

Bevacizumab plus irinotecan in recurrent or progressive malign glioma: a multicenter study of the Anatolian Society of Medical Oncology (ASMO).

PURPOSES: The overall prognosis for recurrent malignant glioma (MG) is extremely poor, and treatment options are limited. We evaluated our multicenter retrospective experience for patients with recurrent MG administering bevacizumab and irinotecan in combination therapy. METHODS: A total of 115 patients with grade IV glial tumor (n = 93) and grade III glial tumor (n = 22) were retrospectively evaluated at 14 centers in Turkey. Primary objectives of the study were to evaluate the efficacy and toxicity of the bevacizumab and irinotecan as salvage treatment based on response to therapy, progression-free survival (PFS), 6 months of PFS, overall survival (OS), and 6 months of OS (OS6). RESULTS: Bevacizumab and irinotecan were performed as second line (79.1 %) and third line treatment (20.9 %). Median chemotherapy cycle was 6 (range 1-37), and median follow-up was 6 months (range 1-36 months). Objective response rate was 39.1 %. Six-month PFS and OS6 were 46.3 % and 67.5 %, respectively. Median PFS was 6 months (95 % CI 2.5-9.5) and 6 months (95 % CI 4.9-7.1) in the grade III and IV groups, respectively (p = 0.773). Median OS was 9 months (95 % CI 7.1-10.9) and 8 months (95 % CI 6.6-9.4) in the grade III and IV groups, respectively (p = 0.450). Serious toxicities were observed in 7.8 % of patients. Treatment-related toxic death was observed in 3 patients. There was no treatment related to central nervous system hemorrhage or other serious hemorrhages. CONCLUSIONS: Present study results were consistent with previous studies. In addition, we detected similar outcomes in grade III and IV glial tumors.

FDG PET/CT appearance of portal vein tumor thrombus in the gastric primitive neuroectodermal tumor: uncommon primary tumor site with rare finding.

Gastric primitive neuroectodermal tumor (PNET) is a very rare tumor. There are only a few case reports in the literature. Although cases with FDG uptake in the portal venous tumor thrombus (PVTT) in different primary malignancies have been evaluated before, the coexistence of PNET and PVTT has not been reported yet. Herein, we report the case of a gastric PNET with PVTT, which resolved after 3 cycles of polychemotherapy except for a residual tumor focus in the gastric corpus.

Takotsubo cardiomyopathy in a patient with lung adenocarcinoma.

Takotsubo cardiomyopathy (TC) is a rare and usually physical or emotional stress-induced clinical disorder characterized by transient left ventricular dysfunction and apical segment ballooning. Much is still unknown regarding risk factors and clinical relationships. Recently, an association between TC and malignancies has been proposed. We present a case of lung adenocarcinoma whose initial hospital admission was due to TC. We contribute this case report to the growing set of literature on the association between TC and malignancies.

Noninvasive assessment of liver fibrosis with the aspartate transaminase to platelet ratio index (APRI): Usefulness in patients with chronic liver disease: APRI in chronic liver disease.

BACKGROUND: The aspartate aminotransferases (AST) to platelet ratio index (APRI) may serve as a noninvasive marker to assess liver fibrosis. OBJECTIVES: To assess the diagnostic ability of the APRI for prediction of fibrosis in patients with chronic hepatitis B (CHB), chronic hepatitis C (CHC), and non-alcoholic fatty liver disease (NAFLD). PATIENTS AND METHODS: This retrospective study included 207 patients with CHB, 108 with CHC, and 140 patients with NAFLD. The APRI was calculated as (AST level/upper normal limit for AST)/platelet counts (109/L) × 100. The stage of liver fibrosis in patients with chronic viral hepatitis was graded using the METAVIR scale. The Kleiner system for grading fibrosis was used in patients with NAFLD. RESULTS: Bivariate correlation analyses showed that the APRI was significantly associated with fibrosis scores in patients with CHC (p = 0.2634, p = 0.0059) and NAFLD (p = 0.2273, p = 0.0069), but not in those with CHB (p = 0.1005, p = 0.1495). Receiver operating characteristic (ROC) curves were used for assessing the ability of the APRI as a predictor of the absence or presence of liver fibrosis (fibrosis score of 0 vs fibrosis scores of 1-4). In patients with CHC, the APRI showed a sensitivity of 72.7% and a specificity of 62.4% for detection of fibrosis (p<0.01). In the NAFLD group, the APRI showed a sensitivity of 60.0% and specificity of 73.3% for detection of fibrosis (p<0.01). In patients with CHB, the APRI showed a sensitivity of 55.0% and a specificity of 75.4% for fibrosis (p=NS). CONCLUSIONS: The APRI shows an acceptable accuracy for the assessment of liver fibrosis in patients with CHC and NAFLD, but not in those with CHB.

Serum levels of vaspin, obestatin, and apelin-36 in patients with nonalcoholic fatty liver disease.

The novel adipokines vaspin, obestatin, and apelin-36 are associated with insulin resistance and the components of the metabolic syndrome. We assayed circulating levels of these molecules and examined their association with clinical, biochemical, and histologic phenotypes in patients with nonalcoholic fatty liver disease (NAFLD). Serum levels of vaspin, obestatin, and apelin-36 were assayed by enzyme-linked immunosorbent assay in 91 patients with biopsy-proven NAFLD and 81 controls. We analyzed associations between adipokines and the characteristics of patients with NAFLD using multivariable linear regression models. Univariable analysis showed that concentrations of vaspin and apelin-36 were significantly higher in patients with NAFLD than in controls, whereas no differences in obestatin levels were found. Serum vaspin levels showed a statistically significant association with C-reactive protein (r = 0.378, P < .001) and liver fibrosis scores (r = 0.401, P < .001), whereas apelin-36 levels showed a modest association with homeostasis model assessment of insulin resistance (r = 0.204, P < .01). After stepwise linear regression analysis, serum vaspin levels were the only independent predictor of liver fibrosis scores in patients with NAFLD (ß = 0.37, t = 3.99, P < .01). Serum vaspin levels are raised in patients with NAFLD regardless of potential confounders and represent an independent predictor of liver fibrosis scores. These findings support further investigation of this novel adipokine in metabolic liver diseases.

Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease.

BACKGROUND: The fibroblast growth factor 21 (FGF21) hormonal pathway is a metabolic signalling cascade and has been recently identified as the master hormonal regulator of glucose, lipids and overall energy balance. In this observational, case-control study, we assayed serum levels of FGF21 in patients with nonalcoholic fatty liver disease (NAFLD), a hepatic manifestation of the metabolic syndrome, and examined their association with clinical, biochemical and histological phenotypes. MATERIALS AND METHODS: Serum levels of FGF21 were assayed by ELISA in 82 patients with biopsy-proven NAFLD and 77 controls. We analysed associations between FGF21 and the characteristics of patients with NAFLD by multiple linear regression analysis. RESULTS: Levels of FGF21 were significantly higher in patients with NAFLD (median 200 pg mL(-1) ; interquartile range: 87-410 pg mL(-1)) than in healthy controls (median 93 pg mL(-1) ; interquartile range: 70-180 pg mL(-1) , Mann-Whitney U-test, P<0·001). There was a stepwise increase in serum FGF21 levels according to the liver steatosis score (median level in subjects with score 1: 170 pg mL(-1) ; score 2: 220 pg mL(-1) ; score 3: 280 pg mL(-1) , P for trend <0·01). After stepwise linear regression analysis, serum FGF21 levels were the only independent predictor of hepatic steatosis scores in patients with NAFLD (ß=0·26; t=2·659, P<0·01). CONCLUSIONS: Serum FGF21 levels are increased in patients with NAFLD regardless of potential confounders and represent an independent predictor of liver steatosis. These findings support further investigation of this molecule in metabolic liver diseases.