Left Ventricular Ejection Fraction in Patients With Ovarian Cancer Treated With Avelumab, Pegylated Liposomal Doxorubicin, or Both.

In the phase III JAVELIN Ovarian 200 trial, 566 patients with platinum-resistant/refractory ovarian cancer were randomized 1:1:1 to receive avelumab alone, avelumab plus pegylated liposomal doxorubicin (PLD), or PLD alone. Cardiac monitoring was included for all patients. We report left ventricular ejection fraction (LVEF) data from the trial. Grade ≥3 cardiac adverse events (AEs) occurred in 4 (2.1%), 1 (0.5%), and 0 patients in the avelumab, combination, and PLD arms, respectively. LVEF decreases of ≥10% to below institutional lower limit of normal at any time during treatment were observed in 1 (0.8%), 3 (1.9%), and 2 (1.5%) patients, respectively; 4 had subsequent assessments, and these showed transient decreases. No patient had a cardiovascular AE related to LVEF decrease. This analysis is, to our knowledge, the first analysis of LVEF in patients receiving immune checkpoint inhibitors. CLINICALTRIALS.GOV IDENTIFIER: NCT02580058.

Avelumab alone or in combination with chemotherapy versus chemotherapy alone in platinum-resistant or platinum-refractory ovarian cancer (JAVELIN Ovarian 200): an open-label, three-arm, randomised, phase 3 study.

BACKGROUND: Most patients with ovarian cancer will relapse after receiving frontline platinum-based chemotherapy and eventually develop platinum-resistant or platinum-refractory disease. We report results of avelumab alone or avelumab plus pegylated liposomal doxorubicin (PLD) compared with PLD alone in patients with platinum-resistant or platinum-refractory ovarian cancer. METHODS: JAVELIN Ovarian 200 was an open-label, parallel-group, three-arm, randomised, phase 3 trial, done at 149 hospitals and cancer treatment centres in 24 countries. Eligible patients were aged 18 years or older with epithelial ovarian, fallopian tube, or peritoneal cancer (maximum of three previous lines for platinum-sensitive disease, none for platinum-resistant disease) and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to avelumab (10 mg/kg intravenously every 2 weeks), avelumab plus PLD (40 mg/m2 intravenously every 4 weeks), or PLD and stratified by disease platinum status, number of previous anticancer regimens, and bulky disease. Primary endpoints were progression-free survival by blinded independent central review and overall survival in all randomly assigned patients, with the objective to show whether avelumab alone or avelumab plus PLD is superior to PLD. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02580058. The trial is no longer enrolling patients and this is the final analysis of both primary endpoints. FINDINGS: Between Jan 5, 2016, and May 16, 2017, 566 patients were enrolled and randomly assigned (combination n=188; PLD n=190, avelumab n=188). At data cutoff (Sept 19, 2018), median duration of follow-up for overall survival was 18·4 months (IQR 15·6-21·9) for the combination group, 17·4 months (15·2-21·3) for the PLD group, and 18·2 months (15·8-21·2) for the avelumab group. Median progression-free survival by blinded independent central review was 3·7 months (95% CI 3·3-5·1) in the combination group, 3·5 months (2·1-4·0) in the PLD group, and 1·9 months (1·8-1·9) in the avelumab group (combination vs PLD: stratified HR 0·78 [repeated 93·1% CI 0·59-1·24], one-sided p=0·030; avelumab vs PLD: 1·68 [1·32-2·60], one-sided p>0·99). Median overall survival was 15·7 months (95% CI 12·7-18·7) in the combination group, 13·1 months (11·8-15·5) in the PLD group, and 11·8 months (8·9-14·1) in the avelumab group (combination vs PLD: stratified HR 0·89 [repeated 88·85% CI 0·74-1·24], one-sided p=0·21; avelumab vs PLD: 1·14 [0·95-1·58], one-sided p=0·83]). The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysesthesia syndrome (18 [10%] in the combination group vs nine [5%] in the PLD group vs none in the avelumab group), rash (11 [6%] vs three [2%] vs none), fatigue (ten [5%] vs three [2%] vs none), stomatitis (ten [5%] vs five [3%] vs none), anaemia (six [3%] vs nine [5%] vs three [2%]), neutropenia (nine [5%] vs nine [5%] vs none), and neutrophil count decreased (eight [5%] vs seven [4%] vs none). Serious treatment-related adverse events occurred in 32 (18%) patients in the combination group, 19 (11%) in the PLD group, and 14 (7%) in the avelumab group. Treatment-related adverse events resulted in death in one patient each in the PLD group (sepsis) and avelumab group (intestinal obstruction). INTERPRETATION: Neither avelumab plus PLD nor avelumab alone significantly improved progression-free survival or overall survival versus PLD. These results provide insights for patient selection in future studies of immune checkpoint inhibitors in platinum-resistant or platinum-refractory ovarian cancer. FUNDING: Pfizer and Merck KGaA, Darmstadt, Germany.

Differential functions of ERK1 and ERK2 in lung metastasis processes in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer characterized by metastasis, drug resistance and high rates of recurrence. With a lack or targeted therapies, TNBC is challenging to treat and carries a poor prognosis. Patients with TNBC tumors expressing high levels of ERK2 have a poorer prognosis than those with low ERK2-expressing tumors. The MAPK pathway is often found to be highly activated in TNBC, however the precise functions of the ERK isoforms (ERK1 and ERK2) in cancer progression have not been well defined. We hypothesized that ERK2, but not ERK1, promotes the cancer stem cell (CSC) phenotype and metastasis in TNBC. Stable knockdown clones of the ERK1 and ERK2 isoforms were generated in SUM149 and BT549 TNBC cells using shRNA lentiviral vectors. ERK2 knockdown significantly inhibited anchorage-independent colony formation and mammosphere formation, indicating compromised self-renewal capacity. This effect correlated with a reduction in migration and invasion. SCID-beige mice injected via the tail vein with ERK clones were employed to determine metastatic potential. SUM149 shERK2 cells had a significantly lower lung metastatic burden than control mice or mice injected with SUM149 shERK1 cells. The Affymetrix HGU133plus2 microarray platform was employed to identify gene expression changes in ERK isoform knockdown clones. Comparison of gene expression levels between SUM149 cells with ERK2 or ERK1 knockdown revealed differential and in some cases opposite effects on mRNA expression levels. Those changes associated with ERK2 knockdown predominantly altered regulation of CSCs and metastasis. Our findings indicate that ERK2 promotes metastasis and the CSC phenotype in TNBC.

Cardiovascular event reduction with PCSK9 inhibition among 1578 patients with familial hypercholesterolemia: Results from the SPIRE randomized trials of bococizumab.

BACKGROUND: Familial hypercholesterolemia (FH) is a dominant genetic disorder associated with elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic events. Although therapeutic monoclonal antibodies that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) are indicated for LDL-C reduction among adult patients with FH, placebo-controlled outcome data among FH patients are scant. OBJECTIVE: Directly compare the efficacy of PCSK9 inhibition as compared to placebo on hard cardiovascular outcomes in FH patients enrolled in the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) program. METHODS: We estimated the efficacy of PCSK9 inhibition with bococizumab on future cardiovascular event rates among 1578 FH patients and 15,959 patients without FH who were selected for comparable lipid levels (on-statin levels of LDL-C >100 mg/dL or non-high-density lipoprotein cholesterol > 130 mg/dL). All patients were randomized by computer generated codes to bococizumab 150 mg subcutaneously every 2 weeks or to matching placebo in the SPIRE clinical trials program and were followed over a median period of 11.2 months for major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death). Analysis is by intention to treat. The SPIRE trials are closed and registered at ClinicalTrials.gov: NCT01968954, NCT01968967, NCT02100514, NCT01968980, NCT01975376, and NCT01975389. RESULTS: Compared to non-FH patients, FH patients enrolled in the SPIRE trials were on average younger (58 vs 63 years), more likely to be women (42 vs 35%), more likely to be primary prevention patients (42 vs 23%), had higher mean baseline LDL-C levels (151 vs 127 mg/dL), and lower rates of diabetes (25 vs 52%) and hypertension (59 vs 82%). FH and non-FH patients both had 55% reductions in LDL-C with bococizumab. Among FH patients, major adverse cardiovascular events occurred among 18 of 781 allocated to bococizumab and 22 of 797 allocated to placebo (hazard ratio 0.83; 95% confidence interval 0.44-1.54, P = .55). This best estimate of effect was similar in magnitude to that observed in the much larger group of patients without FH (hazard ratio 0.79, 95% confidence interval 0.64-0.97, P = .023) with no statistically significant evidence of heterogeneity between groups (P = .87). Incidence rate ratios comparing bococizumab to placebo for adverse events were similar among those with and without FH. The proportion of patients developing antidrug antibodies was higher among those with FH compared to those without FH (43% vs 36%, P < .001). CONCLUSIONS: In these randomized placebo-controlled data, the subgroup of statin-treated FH patients had a similar magnitude of risk reduction for hard cardiovascular events with the PCSK9 inhibitor bococizumab as did patients without FH, with no evidence of statistical heterogeneity between groups.

Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype.

Purpose To determine the long-term prognosis in each phenotypic subset of breast cancer related to residual cancer burden (RCB) after neoadjuvant chemotherapy alone, or with concurrent human epidermal growth factor receptor 2 (HER2)-targeted treatment. Methods We conducted a pathologic review to measure the continuous RCB index (wherein pathologic complete response has RCB = 0; residual disease is categorized into three predefined classes of RCB index [RCB-I, RCB-II, and RCB-III]), and yp-stage of residual disease. Patients were prospectively observed for survival. Three patient cohorts received paclitaxel (T) followed by fluorouracil, doxorubicin, and cyclophosphamide (T/FAC): original development cohort (T/FAC-1), validation cohort (T/FAC-2), and independent validation cohort (T/FAC-3). Another validation cohort received FAC chemotherapy only, and a fifth cohort received concurrent trastuzumab (H) with sequential paclitaxel and fluorouracil, epirubicin, and cyclophosphamide (FEC; H+T/FEC). Phenotypic subsets were defined by hormone receptor (HR) and HER2 status at diagnosis, classified as HR-positive/HER2-negative, HER2-positive (HR-negative/HER2-positive or HR-positive/HER2-positive), or triple receptor-negative. Relapse-free survival estimates were determined from Kaplan-Meier analysis and compared using the log-rank test. Results Five cohorts (T/FAC-1 [n = 219], T/FAC-2 [n = 262], T/FAC-3 [n = 342], FAC [n = 132], and H+T/FEC [n = 203]) had median event-free follow-up of 13.5, 9.1, 6.8, 16.4, and 7.1 years, respectively. Continuous RCB index was prognostic within each phenotypic subset, independent of other clinical-pathologic variables. RCB classes stratified prognostic risk overall, within each phenotypic subset, and within yp-stage categories. Estimates of 10-year relapse-free survival rates in the four RCB classes (pathologic complete response, RCB-I, RCB-II, and RCB-III) were 86%, 81%, 55%, and 23% for triple receptor-negative; 83%, 97%, 74%, and 52% for HR-positive/HER2-negative in the combined T/FAC cohorts; and 95%, 77%, 47%, and 21% in the H+T/FEC cohort. Conclusion RCB was prognostic for long-term survival after neoadjuvant chemotherapy in all three phenotypic subsets of breast cancer. Our institutional findings should be externally validated.

Defining the impact of the use of granulocyte colony stimulating factors on the incidence of chemotherapy-induced neutropenia in patients with gynecologic malignancies.

Purpose The objectives of this study were to characterize the incidence of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN) with specific chemotherapy agents commonly used in the treatment of gynecologic malignancies, as well as defining the impact of granulocyte colony stimulating factors (G-CSF) on the prevention of CIN and FN in this patient population. Methods This retrospective analysis was conducted from a database of 635 gynecologic cancer patients who received chemotherapy between 1 September 2007 and 31 August 2008. A logistic regression analysis was conducted to determine the impact of potential covariates on the overall incidence of CIN. Results Overall, 28.3% of patients experienced CIN with one or more cycles chemotherapy, and 13.1% had treatment delays or dose reduction associated with CIN. The use of G-CSF prior to administration of chemotherapy resulted in a decrease in the incidence of CIN from 29.8% to 19.6% compared to no G-CSF use. No difference was observed in number of treatment delays or dose reductions in the 46 (7.2%) of gynecologic cancer patients that received G-CSF prophylaxis. Multivariate analysis found that both age and the number of current cycles jointly may predict risk of CIN. Conclusions Patients with gynecologic malignancies appear to be at a higher risk of development of neutropenia when treated with chemotherapy. The proactive use of G-CSF did decrease the risk of CIN by over 30%. Prospective study is warranted to determine the impact of G-CSF to reduce CIN in patients with gynecologic malignancies receiving chemotherapy.

Clinical outcomes based on multigene profiling in metastatic breast cancer patients.

BACKGROUND: Identifying the clinical impact of recurrent mutations can help define their role in cancer. Here, we identify frequent hotspot mutations in metastatic breast cancer (MBC) patients and associate them with clinical outcomes. PATIENTS AND METHODS: Hotspot mutation testing was conducted in 500 MBC patients using an 11 gene (N = 126) and/or 46 or 50 gene (N = 391) panel. Patients were stratified by hormone receptor (HR) and human epidermal growth factor 2 (HER2) status. Clinical outcomes were retrospectively collected. RESULTS: Hotspot mutations were most frequently detected in TP53 (30%), PIK3CA (27%) and AKT1 (4%). Triple-negative breast cancer (TNBC) patients had the highest incidence of TP53 (58%) and the lowest incidence of PIK3CA (9%) mutations. TP53 mutation was associated with shorter relapse-free survival (RFS) (median 22 vs 42months; P < 0.001) and overall survival (OS) from diagnosis of distant metastatic disease (median 26 vs 51months; P < 0.001). Conversely, PIK3CA mutation was associated with a trend towards better clinical outcomes including RFS (median 41 vs 30months; P = 0.074) and OS (52 vs 40months; P = 0.066). In HR-positive patients, TP53 mutation was again associated with shorter RFS (median 30 vs 46months; P = 0.017) and OS (median 30 vs 55months; P = 0.001). When multivariable analysis was performed for RFS and OS, TP53 but not PIK3CA mutation remained a significant predictor of outcomes in the overall cohort and in HR-positive patients. CONCLUSIONS: Clinical hotspot sequencing identifies potentially actionable mutations. In this cohort, TP53 mutation was associated with worse clinical outcomes, while PIK3CA mutation did not remain a significant predictor of outcomes after multivariable analysis.

Bayesian Two-stage Biomarker-based Adaptive Design for Targeted Therapy Development.

We propose a Bayesian two-stage biomarker-based adaptive randomization (AR) design for the development of targeted agents. The design has three main goals: (1) to test the treatment efficacy, (2) to identify prognostic and predictive markers for the targeted agents, and (3) to provide better treatment for patients enrolled in the trial. To treat patients better, both stages are guided by the Bayesian AR based on the individual patient's biomarker profiles. The AR in the first stage is based on a known marker. A Go/No-Go decision can be made in the first stage by testing the overall treatment effects. If a Go decision is made at the end of the first stage, a two-step Bayesian lasso strategy will be implemented to select additional prognostic or predictive biomarkers to refine the AR in the second stage. We use simulations to demonstrate the good operating characteristics of the design, including the control of per-comparison type I and type II errors, high probability in selecting important markers, and treating more patients with more effective treatments. Bayesian adaptive designs allow for continuous learning. The designs are particularly suitable for the development of multiple targeted agents in the quest of personalized medicine. By estimating treatment effects and identifying relevant biomarkers, the information acquired from the interim data can be used to guide the choice of treatment for each individual patient enrolled in the trial in real time to achieve a better outcome. The design is being implemented in the BATTLE-2 trial in lung cancer at the MD Anderson Cancer Center.

The BATTLE-2 Study: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer.

PURPOSE: By applying the principles of real-time biopsy, biomarker-based, adaptively randomized studies in non-small-cell lung cancer (NSCLC) established by the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, we conducted BATTLE-2 (BATTLE-2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients With Advanced Non-Small Cell Lung Cancer), an umbrella study to evaluate the effects of targeted therapies focusing on KRAS-mutated cancers. PATIENTS AND METHODS: Patients with advanced NSCLC (excluding sensitizing EGFR mutations and ALK gene fusions) refractory to more than one prior therapy were randomly assigned, stratified by KRAS status, to four arms: (1) erlotinib, (2) erlotinib plus MK-2206, (3) MK-2206 plus AZD6244, or (4) sorafenib. Tumor gene expression profiling-targeted next-generation sequencing was performed to evaluate predictive and prognostic biomarkers. RESULTS: Two hundred patients, 27% with KRAS-mutated (KRAS mut+) tumors, were adaptively randomly assigned to erlotinib (n = 22), erlotinib plus MK-2206 (n = 42), MK-2206 plus AZD6244 (n = 75), or sorafenib (n = 61). In all, 186 patients were evaluable, and the primary end point of an 8-week disease control rate (DCR) was 48% (arm 1, 32%; arm 2, 50%; arm 3, 53%; and arm 4, 46%). For KRAS mut+ patients, DCR was 20%, 25%, 62%, and 44% whereas for KRAS wild-type patients, DCR was 36%, 57%, 49%, and 47% for arms 1, 2, 3, and 4, respectively. Median progression-free survival was 2.0 months, not different by KRAS status, 1.8 months for arm 1, and 2.5 months for arms 2 versus arms 3 and 4 in KRAS mut+ patients (P = .04). Median overall survival was 6.5 months, 9.0 and 5.1 months for arms 1 and 2 versus arms 3 and 4 in KRAS wild-type patients (P = .03). Median overall survival was 7.5 months in mesenchymal versus 5 months in epithelial tumors (P = .02). CONCLUSION: Despite improved progression-free survival on therapy that did not contain erlotinib for KRAS mut+ patients and improved prognosis for mesenchymal tumors, better biomarker-driven treatment strategies are still needed.

TBCRC-010: Phase I/II Study of Dasatinib in Combination with Zoledronic Acid for the Treatment of Breast Cancer Bone Metastasis.

PURPOSE: Osteoclast-mediated bone resorption through src kinase releases growth factors, sustaining bone metastases. This trial determined the recommended phase II dose (RP2D) and clinical efficacy of the src kinase inhibitor dasatinib combined with zoledronic acid in bone predominant, HER2-negative breast cancer metastases. EXPERIMENTAL DESIGN: A 3+3 lead in phase I design confirmed the RP2D allowing activation of the single-arm, phase II trial. Zoledronic acid was administered intravenously on day 1, and dasatinib was given orally once daily for 28 days each cycle as twice daily administration caused dose-limiting toxicity (DLT). Response was assessed every three cycles. N-telopeptide (NTx) was serially measured. RESULTS: A total of 25 patients were enrolled. No DLTs were noted at the RP2D of dasatinib = 100 mg/d. Common adverse events were grade 1-2: rash (9/25, 36%), fatigue (9/25, 36%), pain (9/25, 36%), nausea (6/25, 20%). The objective response rate in bone was 5/22 (23%), all partial responses (PR). The clinical benefit rate [PRs + stable disease (SD) ≥ 6 months] in bone was 8/22 (36%). Median time to treatment failure was 2.70 months [95% confidence interval (CI), 1.84-5.72] in the general cohort, 3.65 months (95% CI, 1.97-7.33) in patients with hormone receptor (HR)-positive breast cancer and 0.70 months (95% CI, 0.30-NA) in those with HR-negative disease. Factors associated with response in bone included lower tumor grade, HR-positive status, and pretreatment high NTx levels. CONCLUSIONS: Combination therapy was well tolerated and produced responses in bone in patients with HR-positive tumors. Clin Cancer Res; 22(23); 5706-12. ©2016 AACR.

miR-141-Mediated Regulation of Brain Metastasis From Breast Cancer.

BACKGROUND: Brain metastasis poses a major treatment challenge and remains an unmet clinical need. Finding novel therapies to prevent and treat brain metastases requires an understanding of the biology and molecular basis of the process, which currently is constrained by a dearth of experimental models and specific therapeutic targets. METHODS: Green Fluorescent Protein (GFP)-labeled breast cancer cells were injected via tail vein into SCID/Beige mice (n = 10-15 per group), and metastatic colonization to the brain and lung was evaluated eight weeks later. Knockdown and overexpression of miR-141 were achieved with lentiviral vectors. Serum levels of miR-141 were measured from breast cancer patients (n = 105), and the association with clinical outcome was determined by Kaplan-Meier method. All statistical tests were two-sided. RESULTS: Novel brain metastasis mouse models were developed via tail vein injection of parental triple-negative and human epidermal growth factor receptor 2 (HER2)-overexpressing inflammatory breast cancer lines. Knockdown of miR-141 inhibited metastatic colonization to brain (miR-141 knockdown vs control: SUM149, 0/8 mice vs 6/9 mice,P= .009; MDA-IBC3, 2/14 mice vs 10/15 mice,P= .007). Ectopic expression of miR-141 in nonexpressing MDA-MB-231 enhanced brain metastatic colonization (5/9 mice vs 0/10 mice,P= .02). Furthermore, high miR-141 serum levels were associated with shorter brain metastasis-free survival (P= .04) and were an independent predictor of progression-free survival (hazard ratio [HR] = 4.77, 95% confidence interval [CI] = 2.61 to 8.71,P< .001) and overall survival (HR = 7.22, 95% CI = 3.46 to 15.06,P< .001). CONCLUSIONS: Our study suggests miR-141 is a regulator of brain metastasis from breast cancer and should be examined as a biomarker and potential target to prevent and treat brain metastases.

Use of a Magnetic Tracer for Sentinel Lymph Node Detection in Early-Stage Breast Cancer Patients: A Meta-analysis.

BACKGROUND: Sentinel lymph node (SLN) dissection involves lymphatic mapping and selective removal of clinically negative lymph nodes at highest risk for harboring metastases. Lymphatic mapping is most often performed using radioisotope with or without blue dye (standard tracers). Sienna+(®), a superparamagnetic iron oxide that can be detected using the Sentimag(®) magnetometer, is an alternative mapping agent to identify SLNs that has been investigated in five clinical trials. This meta-analysis was performed to determine if Sienna+(®) is non-inferior for SLN detection when compared to standard tracers. METHODS: Five clinical trials comparing Sienna+(®) to a standard technique were identified, and data from these studies were used to determine the agreement by Kappa statistic between Sienna+(®) and standard tracers in identifying SLNs and malignant SLNs. The trials included 1683 SLNs identified in 804 patients. Data from the studies were imbalanced, therefore additional agreement indices were utilized to compare techniques. The estimated difference between the techniques was analyzed and a margin of ≤5 % was used to determine non-inferiority. RESULTS: Agreement between the Sienna+(®) and standard tracers was strong for SLN detection by patient [prevalence-adjusted bias-adjusted kappa (PABAK) 0.94, 95 % confidence interval (CI) 0.89-0.98], moderate to substantial for SLN detection by node (PABAK 0.68, 95 % CI 0.54-0.82), and strong for the detection of malignant SLNs by patient (PABAK 0.89, 95 % CI 0.84-0.95). Sienna+(®) demonstrated non-inferiority compared with standard tracers. CONCLUSIONS: The Sienna+(®) mapping agent is non-inferior to the standard method for SLN detection in patients with clinically node-negative breast cancer.

Impact of a Biomarker-Based Strategy on Oncology Drug Development: A Meta-analysis of Clinical Trials Leading to FDA Approval.

BACKGROUND: In order to ascertain the impact of a biomarker-based (personalized) strategy, we compared outcomes between US Food and Drug Administration (FDA)-approved cancer treatments that were studied with and without such a selection rationale. METHODS: Anticancer agents newly approved (September 1998 to June 2013) were identified at the Drugs@FDA website. Efficacy, treatment-related mortality, and hazard ratios (HRs) for time-to-event endpoints were analyzed and compared in registration trials for these agents. All statistical tests were two-sided. RESULTS: Fifty-eight drugs were included (leading to 57 randomized [32% personalized] and 55 nonrandomized trials [47% personalized], n = 38 104 patients). Trials adopting a personalized strategy more often included targeted (100% vs 65%, P < .001), oral (68% vs 35%, P = .001), and single agents (89% vs 71%, P = .04) and more frequently permitted crossover to experimental treatment (67% vs 28%, P = .009). In randomized registration trials (using a random-effects meta-analysis), personalized therapy arms were associated with higher relative response rate ratios (RRRs, compared with their corresponding control arms) (RRRs = 3.82, 95% confidence interval [CI] = 2.51 to 5.82, vs RRRs = 2.08, 95% CI = 1.76 to 2.47, adjusted P = .03), longer PFS (hazard ratio [HR] = 0.41, 95% CI = 0.33 to 0.51, vs HR = 0.59, 95% CI = 0.53 to 0.65, adjusted P < .001) and a non-statistically significantly longer OS (HR = 0.71, 95% CI = 0.61 to 0.83, vs HR = 0.81, 95% CI = 0.77 to 0.85, adjusted P = .07) compared with nonpersonalized trials. Analysis of experimental arms in all 112 registration trials (randomized and nonrandomized) demonstrated that personalized therapy was associated with higher response rate (48%, 95% CI = 42% to 55%, vs 23%, 95% CI = 20% to 27%, P < .001) and longer PFS (median = 8.3, interquartile range [IQR] = 5 vs 5.5 months, IQR = 5, adjusted P = .002) and OS (median = 19.3, IQR = 17 vs 13.5 months, IQR = 8, Adjusted P = .04). A personalized strategy was an independent predictor of better RR, PFS, and OS, as demonstrated by multilinear regression analysis. Treatment-related mortality rate was similar for personalized and nonpersonalized trials. CONCLUSIONS: A biomarker-based approach was safe and associated with improved efficacy outcomes in FDA-approved anticancer agents.

Stromal Cells Derived from Visceral and Obese Adipose Tissue Promote Growth of Ovarian Cancers.

Obesity, and in particular visceral obesity, has been associated with an increased risk of developing cancers as well as higher rates of mortality following diagnosis. The impact of obesity on adipose-derived stromal cells (ASC), which contribute to the formation of tumor stroma, is unknown. Here we hypothesized that visceral source and diet-induced obesity (DIO) changes the ASC phenotype, contributing to the tumor promoting effects of obesity. We found that ASC isolated from subcutaneous (SC-ASC) and visceral (V-ASC) white adipose tissue(WAT) of lean(Le) and obese(Ob) mice exhibited similar mesenchymal cell surface markers expression, and had comparable effects on ovarian cancer cell proliferation and migration. Obese and visceral derived ASC proliferated slower and exhibited impaired differentiation into adipocytes and osteocytes in vitro as compared to ASC derived from subcutaneous WAT of lean mice. Intraperitoneal co-injection of ovarian cancer cells with obese or visceral derived ASC, but not lean SC-ASC, increased growth of intraperitoneal ID8 tumors as compared to controls. Obese and V-ASC increased stromal infiltration of inflammatory cells, including CD3+ T cells and F4/80+ macrophages. Obese and visceral derived ASC, but not lean SC-ASC, increased expression of chemotactic factors IL-6, MIP-2, and MCP-1 when cultured with tumor cells. Overall, these results demonstrate that obese and V-ASC have a unique phenotype, with more limited proliferation and differentiation capacity but enhanced expression of chemotactic factors in response to malignant cells which support infiltration of inflammatory cells and support tumor growth and dissemination.

Epithelial to mesenchymal transition is associated with rapamycin resistance.

Rapamycin analogues have antitumor efficacy in several tumor types, however few patients demonstrate tumor regression. Thus, there is a pressing need for markers of intrinsic response/resistance and rational combination therapies. We hypothesized that epithelial-to-mesenchymal transition (EMT) confers rapamycin resistance. We found that the epithelial marker E-cadherin protein is higher in rapamycin sensitive (RS) cells and mesenchymal breast cancer cell lines selected by transcriptional EMT signatures are less sensitive to rapamycin. MCF7 cells, transfected with constitutively active mutant Snail, had increased rapamycin resistance (RR) compared to cells transfected with wild-type Snail. Conversely, we transfected two RR mesenchymal cell lines-ACHN and MDA-MB-231-with miR-200b/c or ZEB1 siRNA to promote mesenchymal-to-epithelial transition. This induced E-cadherin expression in both cell lines, and ACHN demonstrated a significant increase in RS. Treatment of ACHN and MDA-MB-231 with trametinib modulated EMT in ACHN cells in vitro. Treatment of MDA-MB-231 and ACHN xenografts with trametinib in combination with rapamycin resulted in significant growth inhibition in both but without an apparent effect on EMT. Future studies are needed to determine whether EMT status is predictive of sensitivity to rapalogs and to determine whether combination therapy with EMT modulating agents can enhance antitumor effects of PI3K/mTOR inhibitors.

A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer.

PURPOSE: Low molecular weight cyclin E (LMW-E) isoforms, overexpressed in a majority (~70 %) of triple-negative breast cancers (TNBC), were found in preclinical models to mediate tumorigenesis through binding and activation of CDK2. CDK1/CDK2 inhibitors, such as dinaciclib, combined with anthracyclines, were synergistic in decreasing viability of TNBC cell lines. Based on this data, a phase 1 study was conducted to determine the maximum tolerated dose of dinaciclib in combination with epirubicin in patients with metastatic TNBC. METHODS: Cohorts of at least 2 patients were treated with escalating doses of dinaciclib given on day 1 followed by standard dose of epirubicin given on day 2 of a 21 day cycle. No intra-patient dose escalation was allowed. An adaptive accrual design based upon toxicity during cycle 1 determined entry into therapy cohorts. The target acceptable dose limiting toxicity (DLT) to advance to the next treatment level was 30 %. RESULTS: Between 9/18/2012 and 7/18/2013, 9 patients were enrolled and treated at MD Anderson Cancer Center. DLTs included febrile neutropenia (grade 3, n = 2), syncope (grade 3, n = 2) and vomiting (grade 3, n = 1). Dose escalation did not proceed past the second cohort due to toxicity. After further accrual, the first dose level was also found to be too toxic. No treatment responses were noted, median time to progression was 5.5 weeks (range 3-12 weeks). Thus, accrual was stopped rather than explore the -1 dose level. CONCLUSION: The combination of dinaciclib and epirubicin is associated with substantial toxicities and does not appear to be an effective treatment option for TNBC.

Phase I study of the anti-IGF1R antibody cixutumumab with everolimus and octreotide in advanced well-differentiated neuroendocrine tumors.

Preclinical data suggest multiple roles for the IGF1 receptor (IGF1R) in neuroendocrine tumors (NETs), including mediating resistance to mammalian target of rapamycin (mTOR) inhibitors. Everolimus, an oral mTOR inhibitor, and octreotide long-acting repeatable (LAR) are approved for subgroups of well-differentiated NET. The primary objective of the present study was to establish the safety and recommended phase II dose (RP2D) of cixutumumab, a monoclonal antibody (MAB) against IGF1R, with everolimus and octreotide LAR. Patients with well-differentiated NET were treated with 10  mg everolimus p.o. daily, 20  mg octreotide LAR i.m. every 21 days, and escalating doses of cixutumumab. An expansion cohort was enrolled at RP2D. Correlative studies included the evaluation of mTOR pathway inhibition in paired tumor biopsies and the effects of this combination on metabolism via indirect calorimetry. Nineteen patients with progressive disease were enrolled, including nine to the expansion portion. Two patients had dose-limiting toxicities of grade 3 mucositis at 15  mg/kg cixutumumab. Long-term tolerance at RP2D was problematic, and the most common ≥grade 3 adverse event was fatigue. One patient with metastatic insulinoma had a confirmed partial response, whereas 17 had stable disease. The median progression-free survival was 43.6 weeks, and the median overall survival was 25.5 months. The RP2D of this combination per the predefined study protocol of 10  mg/kg cixutumumab i.v., 20  mg octreotide LAR i.m. every 21 days plus 10  mg everolimus p.o. daily is associated with non-dose-limiting toxicities that limit long-term tolerance. Although a signal of activity was noted in the present study, this will need to be reconciled with limited tolerance of the combination and data from larger studies of anti-IGF1R MABs in NET that have been disappointing.

Association of Body Mass Index Changes during Neoadjuvant Chemotherapy with Pathologic Complete Response and Clinical Outcomes in Patients with Locally Advanced Breast Cancer.

The purpose of this study was to determine the association between body mass index (BMI) measurements (baseline BMI and changes in BMI during neoadjuvant systemic treatment [NST]) and clinical efficacy (pathologic complete response [pCR] rate and survival outcomes) in locally advanced breast cancer (LABC). We hypothesized that high baseline BMI and increases in BMI during NST are associated with lower pCR rates and poorer clinical outcomes in LABC. We retrospectively reviewed the medical records of 1002 patients, 204 with primary inflammatory breast cancer (IBC) and 798 with stage III non-IBC, who underwent standard NST and definitive surgery between November 1, 2006, and December 31, 2012. The median follow-up time for the survivors was 19.6 months (0.4 - 67.8 months). The pCR rates of patients whose BMI increased or decreased were 23.2% and 18.1%, respectively, (p=0.048). The unadjusted overall survival (OS) was significantly better in the group with increased BMI (p=0.006). However, increased BMI was not an independent predictor of pCR and clinical outcomes (recurrence-free survival and OS) after adjusting for other clinical variables. In subset analyses, increased BMI as a continuous variable was an independent predictor of higher pCR rates in the normal BMI/underweight group (odds ratio [OR]=1.35, 95% confidence interval [CI]: 1.06-0.71, p=0.015). Increased BMI (BMI change ≥0 vs. <0) was also an independent predictor of pCR (OR=1.65, 95% CI: 1.00-2.72, p=0.049) in the postmenopausal group. Our results show that increasing BMI shows improved clinical outcome in terms of better pCR rates in normal BMI/underweight group and in the postmenopausal group. These results contradict previously reported findings on the association between high BMI and poor clinical efficacy regarding pCR rate and survival outcomes in early-stage breast cancer. Thus, the role of BMI in breast cancer may depend on patients' clinical characteristics such as advanced stage.

The effect of extracorporeal photopheresis alone or in combination therapy on circulating CD4(+) Foxp3(+) CD25(-) T cells in patients with leukemic cutaneous T-cell lymphoma.

PURPOSE: Extracorporeal photopheresis (ECP) alone or in combination therapy is effective for treatment of leukemic cutaneous T-cell lymphoma (L-CTCL), but its mechanism(s) of action remain unclear. This study was designed to investigate the effect of ECP on regulatory T cells and CD8(+) T cells in L-CTCL patients. EXPERIMENTAL DESIGN: Peripheral blood from 18 L-CTCL patients at baseline, Day 2, 1 month, 3 month, and 6 month post-ECP therapy was analyzed by flow cytometry for CD4(+) CD25(+/high) , CD4(+) Foxp3(+) CD25(+/-) , CD3(+) CD8(+) , CD3(+) CD8(+) CD69(+) , and CD3(+) CD8(+) IFN-γ(+) T cells. Clinical responses were assessed and correlated with changes in these T-cell subsets. RESULTS: Twelve of 18 patients achieved clinical responses. The average baseline number of CD4(+) CD25(+/high) T cells of PBMCs in L-CTCL patients was normal (2.2%), but increased at 6-month post-therapy (4.3%, P < 0.01). The average baseline number of CD4(+) Foxp3(+) T cells out of CD4(+) T cells in nine evaluable patients was high (66.8 ± 13.7%), mostly CD25 negative. The levels of CD4(+) Foxp3(+) T cells in responders were higher (n = 6, 93.1 ± 5.7%) than nonresponders (n = 3, 14.2 ± 16.0%, P < 0.01), and they declined in parallel with malignant T cells. The numbers of CD3(+) CD8(+) CD69(+) and CD3(+) CD8(+) IFN-γ(+) T cells increased at 3-month post-therapy in five of six patients studied. CONCLUSIONS: Extracorporeal photopheresis alone or in combination therapy might be effective in L-CTCL patients whose malignant T cells have a CD4(+) Foxp3(+) CD25(-) phenotype.