Showing papers by "Marek Ancukiewicz published in 2012"
TL;DR: It is demonstrated that targeting tumor vasculature with lower vascular-normalizing doses, but not high antivascular/antiangiogenic doses, of an anti-VEGF receptor 2 (VEGFR2) antibody results in a more homogeneous distribution of functional tumor vessels.
Abstract: The recent approval of a prostate cancer vaccine has renewed hope for anticancer immunotherapies. However, the immunosuppressive tumor microenvironment may limit the effectiveness of current immunotherapies. Antiangiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy, but they often are used at high doses in the clinic to prune tumor vessels and paradoxically may compromise various therapies. Here, we demonstrate that targeting tumor vasculature with lower vascular-normalizing doses, but not high antivascular/antiangiogenic doses, of an anti-VEGF receptor 2 (VEGFR2) antibody results in a more homogeneous distribution of functional tumor vessels. Furthermore, lower doses are superior to the high doses in polarizing tumor-associated macrophages from an immune inhibitory M2-like phenotype toward an immune stimulatory M1-like phenotype and in facilitating CD4+ and CD8+ T-cell tumor infiltration. Based on this mechanism, scheduling lower-dose anti-VEGFR2 therapy with T-cell activation induced by a whole cancer cell vaccine therapy enhanced anticancer efficacy in a CD8+ T-cell–dependent manner in both immune-tolerant and immunogenic murine breast cancer models. These findings indicate that vascular-normalizing lower doses of anti-VEGFR2 antibody can reprogram the tumor microenvironment away from immunosuppression toward potentiation of cancer vaccine therapies. Given that the combinations of high doses of bevacizumab with chemotherapy have not improved overall survival of breast cancer patients, our study suggests a strategy to use antiangiogenic agents in breast cancer more effectively with active immunotherapy and potentially other anticancer therapies.
763 citations
TL;DR: In an analysis of frozen tissue specimens, IDH1 mutation was associated with highly elevated tissue levels of the enzymatic product 2-hydroxyglutarate, defining a specific metabolic abnormality in this largely incurable type of gastrointestinal cancer and present a potentially new target for therapy.
Abstract: Cancers of origin in the gallbladder and bile ducts are rarely curable with current modalities of cancer treatment. Our clinical application of broad-based mutational profiling for patients diagnosed with a gastrointestinal malignancy has led to the novel discovery of mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) in tumors from a subset of patients with cholangiocarcinoma. A total of 287 tumors from gastrointestinal cancer patients (biliary tract, colorectal, gastroesophageal, liver, pancreatic, and small intestine carcinoma) were tested during routine clinical evaluation for 130 site-specific mutations within 15 cancer genes. Mutations were identified within a number of genes, including KRAS (35%), TP53 (22%), PIK3CA (10%), BRAF (7%), APC (6%), NRAS (3%), AKT1 (1%), CTNNB1 (1%), and PTEN (1%). Although mutations in the metabolic enzyme IDH1 were rare in the other common gastrointestinal malignancies in this series (2%), they were found in three tumors (25%) of an initial series of 12 biliary tract carcinomas. To better define IDH1 and IDH2 mutational status, an additional 75 gallbladder and bile duct cancers were examined. Combining these cohorts of biliary cancers, mutations in IDH1 and IDH2 were found only in cholangiocarcinomas of intrahepatic origin (nine of 40, 23%) and in none of the 22 extrahepatic cholangiocarcinomas and none of the 25 gallbladder carcinomas. In an analysis of frozen tissue specimens, IDH1 mutation was associated with highly elevated tissue levels of the enzymatic product 2-hydroxyglutarate. Thus, IDH1 mutation is a molecular feature of cholangiocarcinomas of intrahepatic origin. These findings define a specific metabolic abnormality in this largely incurable type of gastrointestinal cancer and present a potentially new target for therapy.
640 citations
TL;DR: TGF-β blockade improved the intratumoral penetration of both a low-molecular-weight conventional chemotherapeutic drug and a nanotherape therapeutic agent, leading to better control of tumor growth.
Abstract: Although the role of TGF-β in tumor progression has been studied extensively, its impact on drug delivery in tumors remains far from understood. In this study, we examined the effect of TGF-β blockade on the delivery and efficacy of conventional therapeutics and nanotherapeutics in orthotopic mammary carcinoma mouse models. We used both genetic (overexpression of sTβRII, a soluble TGF-β type II receptor) and pharmacologic (1D11, a TGF-β neutralizing antibody) approaches to block TGF-β signaling. In two orthotopic mammary carcinoma models (human MDA-MB-231 and murine 4T1 cell lines), TGF-β blockade significantly decreased tumor growth and metastasis. TGF-β blockade also increased the recruitment and incorporation of perivascular cells into tumor blood vessels and increased the fraction of perfused vessels. Moreover, TGF-β blockade normalized the tumor interstitial matrix by decreasing collagen I content. As a result of this vessel and interstitial matrix normalization, TGF-β blockade improved the intratumoral penetration of both a low-molecular-weight conventional chemotherapeutic drug and a nanotherapeutic agent, leading to better control of tumor growth.
281 citations
TL;DR: MRI is used to assess tumor blood perfusion in 30 recurrent glioblastoma patients who were undergoing treatment with cediranib, a pan-VEGF receptor tyrosine kinase inhibitor to offer direct clinical evidence in support of the hypothesis that vascular normalization can increase tumor perfusion and help improve patient survival.
Abstract: The abnormal vasculature of the tumor microenvironment supports progression and resistance to treatment. Judicious application of anti-angiogenic therapy may normalize the structure and function of the tumor vasculature, promoting improved blood perfusion. However, there has been a lack of direct clinical evidence for improvements in blood perfusion after anti-angiogenic therapy. In this study, we used MRI to assess tumor blood perfusion in 30 recurrent glioblastoma patients who were undergoing treatment with cediranib, a pan-VEGF receptor tyrosine kinase inhibitor. Tumor blood perfusion increased durably for more than one month in 7of 30 patients where it was associated with longer survival. Together, our findings offer direct clinical evidence in support of the hypothesis that vascular normalization promotes tumor regression and longer patient survival.
266 citations
TL;DR: In this paper, the authors evaluated arm measurements of breast cancer patients to critically assess absolute change in arm size compared to relative arm volume change as criteria for quantifying breast cancer-related lymphedema (BCRL).
Abstract: The purpose of this article is to evaluate arm measurements of breast cancer patients to critically assess absolute change in arm size compared to relative arm volume change as criteria for quantifying breast cancer-related lymphedema (BCRL). We used pre-operative measurements of 677 patients screened for BCRL before and following treatment of unilateral breast cancer at Massachusetts General Hospital between 2005 and 2008 to model the effect of an absolute change in arm size of 200 mL or 2 cm compared to relative arm volume change. We also used sequential measurements to analyze temporal variation in unaffected arm volume. Pre-operative arm volumes ranged from 1,270 to 6,873 mL and correlated strongly (Kendall’s τ = 0.55) with body mass index (BMI). An absolute arm volume change of 200 mL corresponded to relative arm volume changes ranging from 2.9 to 15.7 %. In a subset of 45 patients, modeling of a 2-cm change in arm circumference predicted relative arm volume changes ranging from 6.0 to 9.8 %. Sequential measurements of 124 patients with >6 measurements demonstrated remarkable temporal variation in unaffected arm volume (median within-patient change 10.5 %). The magnitude of such fluctuations correlated (τ = 0.36, P .05). Absolute changes in arm size used as criteria for BCRL are correlated with pre-operative and temporal changes in body size. Therefore, utilization of absolute volume or circumference change in clinical trials is flawed because specificity depends strongly on patient body size. Relative arm volume change is independent of body size and should thus be used as the standard criterion for diagnosis of BCRL.
68 citations
TL;DR: Low-dose-rate accelerated partial breast irradiation with implant brachytherapy provides acceptable local control in select early-stage BCa patients, however, treatment-related toxicity and cosmetic complications were significant with longer follow-up and at higher doses.
Abstract: Purpose To evaluate the long-term toxicity, cosmesis, and local control of accelerated partial breast irradiation with implant brachytherapy after wide local excision for Stage T1N0 breast cancer (BCa) Materials and Methods Between 1997 and 2001, 50 patients with Stage T1N0M0 BCa were treated in a Phase I-II protocol using low-dose-rate accelerated partial breast irradiation with implant brachytherapy after wide local excision and lymph node surgery The total dose was escalated in three groups: 50 Gy (n = 20), 55 Gy (n = 17), and 60 Gy (n = 13) Patient- and physician-assessed breast cosmesis, patient satisfaction, toxicity, mammographic abnormalities, repeat biopsies, and disease status were prospectively evaluated at each visit Kendall's tau (τ β ) and logistic regression analyses were used to correlate outcomes with dose, implant volume, patient age, and systemic therapy Results The median follow-up period was 112 years (range, 4–14) The patient satisfaction rate was 67%, 67% reported good-excellent cosmesis, and 54% had moderate-severe fibrosis Higher dose was correlated with worse cosmetic outcome (τ β 06, p β 05, p β 04, p = 0024) Of the 50 patients, 35% had fat necrosis and 34% developed telangiectasias ≥1 cm 2 Grade 3–4 late skin and subcutaneous toxicities were seen in 4 patients (9%) and 6 patients (13%), respectively, and both correlated with higher dose (τ β 03–05, p ≤ 01) One patient had Grade 4 skin ulceration and fat necrosis requiring surgery Mammographic abnormalities were seen in 32% of the patients, and 30% underwent repeat biopsy, of which 73% were benign Six patients had ipsilateral breast recurrence: five elsewhere in the breast, and one at the implant site One patient died of metastatic BCa after recurrence The 12-year actuarial local control, recurrence-free survival, and overall survival rate was 85% (95% confidence interval, 70–97%), 72% (95% confidence interval, 54–86%), and 87% (95% confidence interval, 73–99%), respectively Conclusion Low-dose-rate accelerated partial breast irradiation with implant brachytherapy provides acceptable local control in select early-stage BCa patients However, treatment-related toxicity and cosmetic complications were significant with longer follow-up and at higher doses
64 citations
TL;DR: These men were characterized by elevations in several traditional markers of aggressive disease and also by higher levels of several inflammatory biomarkers, which indicate the role of these biomarkers should be further explored.
Abstract: Introduction. Angiogenesis and inflammation are both important to the pathogenesis of malignancies. Androgen deprivation therapy (ADT) for prostate cancer causes drastic hormonal changes that alter both disease and host factors. We measured inflammatory and angiogenic biomarkers in ADT-treated and control groups of men with prostate cancer. Materials and Methods. Baseline and 12-week plasma samples were collected from 37 ADT-naive men with locally advanced or recurrent prostate cancer. Of those, 23 initiated ADT with a gonadotropin-releasing hormone (GnRH) agonist and 14 served as nontreatment controls. Samples were tested for a panel of angiogenic and inflammatory biomarkers. Results. The treatment group had significantly higher concentrations of the inflammatory biomarkers interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor (TNF)-, and stromal cell–derived factor (SDF)-1. None of the angiogenic biomarkers were significantly different between the groups at baseline. Among patients with a short prostate-specific antigen (PSA) doubling time (<6 months), the proangiogenic factor basic fibroblast growth factor (bFGF) was lower at baseline. In the treatment group, plasma placental growth factor (PlGF) increased and IL-6 decreased after 12 weeks of ADT. Moreover, the treatment group continued to have significantly higher concentrations of the inflammatory biomarkers IL-1, IL-8, and SDF-1 as well as bFGF than controls. Discussion. These men were characterized by elevations in several traditional markers of aggressive disease and also by higher levels of several inflammatory biomarkers. Although ADT decreased IL-6 levels, IL-1, IL-8, and SDF-1 remained significantly higher than in controls. The role of these biomarkers should be further explored. The Oncologist 2012;17:212–219
49 citations
TL;DR: Patients with triple-negative breast cancer had a significantly higher IBTR rate than patients with other receptor phenotypes when treated with 3D-APBI, and overall outcomes were excellent, particularly for patients with estrogen receptor-positive disease.
Abstract: Purpose External beam accelerated partial breast irradiation (APBI) is an increasingly popular technique for treatment of patients with early stage breast cancer following breast-conserving surgery. Here we present 5-year results of a prospective trial. Methods and Materials From October 2003 through November 2005, 98 evaluable patients with stage I breast cancer were enrolled in the first dose step (32 Gy delivered in 8 twice-daily fractions) of a prospective, multi-institutional, dose escalation clinical trial of 3-dimensional conformal external beam APBI (3D-APBI). Median age was 61 years; median tumor size was 0.8 cm; 89% of tumors were estrogen receptor positive; 10% had a triple-negative phenotype; and 1% had a HER-2-positive subtype. Median follow-up was 71 months (range, 2-88 months; interquartile range, 64-75 months). Results Five patients developed ipsilateral breast tumor recurrence (IBTR), for a 5-year actuarial IBTR rate of 5% (95% confidence interval [CI], 1%-10%). Three of these cases occurred in patients with triple-negative disease and 2 in non-triple-negative patients, for 5-year actuarial IBTR rates of 33% (95% CI, 0%-57%) and 2% (95% CI, 0%-6%; P P =.0537). Conclusions Overall outcomes were excellent, particularly for patients with estrogen receptor-positive disease. Patients in this study with triple-negative breast cancer had a significantly higher IBTR rate than patients with other receptor phenotypes when treated with 3D-APBI. Larger, prospective 3D-APBI clinical trials should continue to evaluate the effect of hormone receptor phenotype on IBTR rates.
48 citations
TL;DR: Vandetanib can be safely combined with cetuximab and irinotecan for metastatic colorectal cancer and differential effects on certain plasma biomarkers for VEGFR inhibition when combined with EGFR blockade and a potential correlation between baseline sVEGFR1 and response are suggested.
Abstract: Background
To determine the maximum tolerated dose (MTD) and safety, and explore efficacy and biomarkers of vandetanib with cetuximab and irinotecan in second-line metastatic colorectal cancer.
44 citations
TL;DR: Pretreatment intra-tumoral IFP correlated with tumor size and decreased in two evaluable patients with SD on sorafenib, and induced changes in circulating biomarkers consistent with expected VEGF pathway blockade, despite the lack of more striking clinical activity in this small series.
Abstract: Purpose: Sorafenib is a multi-targeted tyrosine kinase inhibitor with therapeutic efficacy in several malignancies. Sorafenib may exert its anti-neoplastic effect in part by altering vascular permeability and reducing intra-tumoral interstitial hypertension. As correlative science with a phase II study in patients with advanced soft-tissue sarcomas (STS), we evaluated the impact of this agent on intra-tumor interstitial fluid pressure (IFP), serum circulating biomarkers, and vascular density. Patients and Methods: Patients with advanced STS with measurable disease and at least one superficial lesion amenable to biopsy received sorafenib 400 mg twice daily. Intratumoral IFP and plasma and circulating cell biomarkers were measured before and after 1–2 months of sorafenib administration. Results were analyzed in the context of the primary clinical endpoint of time-to-progression (TTP). Results: In 15 patients accrued, the median TTP was 45 days (range 14–228). Intra-tumoral IFP measurements obtained in 6 patients at baseline showed a direct correlation with tumor size. Two patients with stable disease at two months had postsorafenib IFP evaluations and demonstrated a decline in IFP and vascular density. Sorafenib significantly increased plasma VEGF, PlGF, and SDF1a and decreased sVEGFR-2 levels. Increased plasma SDF1a and decreased sVEGFR-2 levels on day 28 correlated with disease progression. Conclusions: Pretreatment intra-tumoral IFP correlated with tumor size and decreased in two evaluable patients with SD on sorafenib. Sorafenib also induced changes in circulating biomarkers consistent with expected VEGF pathway blockade, despite the lack of more striking clinical activity in this small series. Trial Registration: ClinicalTrials.gov NCT00330421
40 citations
TL;DR: In this paper, the association between functional single-nucleotide polymorphisms in candidate genes from oxidative stress pathways and risk of radiation pneumonitis (RP) in patients treated with thoracic radiation therapy for locally advanced lung cancer was examined.
Abstract: BACKGROUND:
This study examined the association between functional single-nucleotide polymorphisms in candidate genes from oxidative stress pathways and risk of radiation pneumonitis (RP) in patients treated with thoracic radiation therapy for locally advanced lung cancer.
METHODS:
A review was conducted of 136 patients treated with radiation therapy for lung cancer between 2001 and 2007, and who had prior genotyping of functional single-nucleotide polymorphisms in oxidative stress genes including superoxide dismutase 2 (SOD2; rs4880) and methylene tetrahydrofolate reductase (MTHFR; rs1801131, rs1801133). RP events were retrospectively scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Cox proportional hazard regression was performed to identify clinical variables and genotypes associated with risk of RP of grades ≥2 and ≥3 on univariate and multivariate analysis, respectively. P values were corrected for multiple hypothesis esting.
RESULTS:
With a median follow-up of 21.4 months, the incidence of grade ≥2 RP was 29% and grade ≥3 RP was 14%. On multivariate analysis, after adjusting for clinical factors such as concurrent chemotherapy and consolidation docetaxel, and lung dosimetric parameters such as volume receiving greater than 20 Gy and mean lung dose, MTHFR genotype (rs1801131; AA versus AC/CC) was significantly associated with risk of grade ≥2 RP (hazard ratio: 0.37; 95% confidence interval: 0.18-0.76; P = .006, corrected P = .018) and grade ≥3 RP (hazard ratio: 0.21; 95% confidence interval: 0.06-0.70; P = .01; corrected P = .03). SOD2 genotype was not associated with RP.
CONCLUSIONS:
This study showed an association between MTHFR genotype and risk of clinically significant RP. Further study of MTHFR-related pathways may provide insight into the mechanisms behind RP. Cancer 2012;3654–3665. © 2011 American Cancer Society.
TL;DR: The results are consistent with prior studies with physician-assessed acute toxicity, and they identify small bowel V15 as an important predictor of acute GI symptoms during 5-FU-based chemoradiation treatment for rectal cancer.
Abstract: Purpose Research on patient-reported outcomes (PROs) in rectal cancer is limited. We examined whether dose–volume parameters of the small bowel and large bowel were associated with patient-reported gastrointestinal (GI) symptoms during 5-fluorouracil (5-FU)–based chemoradiation treatment for rectal cancer. Methods and Materials 66 patients treated at the Brigham & Women's Hospital or Massachusetts General Hospital between 2006 and 2008 were included. Weekly during treatment, patients completed a questionnaire assessing severity of diarrhea, urgency, pain, cramping, mucus, and tenesmus. The association between dosimetric parameters and changes in overall GI symptoms from baseline through treatment was examined by using Spearman's correlation. Potential associations between these parameters and individual GI symptoms were also explored. Results The amount of small bowel receiving at least 15 Gy (V15) was significantly associated with acute symptoms ( p = 0.01), and other dosimetric parameters ranging from V5 to V45 also trended toward association. For the large bowel, correlations between dosimetric parameters and overall GI symptoms at the higher dose levels from V25 to V45 did not reach statistical significance ( p = 0.1), and a significant association was seen with rectal pain from V15 to V45 ( p Conclusions The results of this study using PROs are consistent with prior studies with physician-assessed acute toxicity, and they identify small bowel V15 as an important predictor of acute GI symptoms during 5-FU–based chemoradiation treatment. A better understanding of the relationship between radiation dosimetric parameters and PROs may allow physicians to improve radiation planning to optimize patient outcomes.
TL;DR: A unique preop trial with a run-in of single agent bev followed by ddACT with bev in two cohorts, one with HR+HER2– BC, and a smaller triple negative (TN) cohort, to facilitate the identification of BCs most likely to benefit from bev.
Abstract: 1026 Background: Two recent preop studies evaluating bev showed conflicting results, particularly in hormone receptor (HR)+ BC. Identification of predictive markers and their relationship to the ph...
TL;DR: The tolerability, efficacy and potential mechanism of action of radiation, temozolomide, and cediranib in newly diagnosed glioblastoma patients was evaluated and no dose-limiting toxicities were identified.
Abstract: 2009 Background: Anti-angiogenic therapy is hypothesized to synergize with radiation and chemotherapy by improving tumor blood flow. We evaluated the tolerability, efficacy and potential mechanism ...
TL;DR: A phase II study of cediranib (AZD2171)—a more potent and selective pan-VEGF receptor inhibitor—in advanced HCC patients, which enrolled the targeted 17 pts required for the first stage of the planned study.
Abstract: 4112 Background: Sorafenib remains the only approved systemic therapy in HCC. We performed a phase II study of cediranib (AZD2171)—a more potent and selective pan-VEGF receptor inhibitor—in advanced HCC patients (pts). Methods: Eligibility criteria included unresectable or metastatic measurable HCC, ECOG PS ≤2, CLIP score ≤3, and adequate organ function. Patients received cediranib at 30 mg po qd continuously (4-wk cycle). The primary endpoint was progression free survival (PFS). We also assessed overall survival (OS) and response rates, steady-state PK of cediranib, and blood circulating biomarkers. Results: Since 6/16/09, we have enrolled the targeted 17 pts required for the first stage of the planned study: ECOG 0/1/2=5/11/1, CLIP 1/2/3=6/4/7, Child A/B=14/3, BCLC C=17. Nine pts had prior sorafenib. The best response was stable disease in five pts (29%). The median PFS was 5.3 months (95% CI: 3.5-9.7). The median OS was 11.7 months (95% CI: 7.5-13.6). Grade 3 toxicities included hypertension (29%), hyp...
TL;DR: To examine the role of TAMs in recurrent GBM, autopsy specimens from patients with or without history of antiangiogenic therapy were analyzed and TAMs were morphologically and phenotypically identified with flow cytometry and immunohistochemistry.
Abstract: 2010 Background: Antiangiogenic therapy is associated with increased radiographic responses in glioblastoma (GBM), but tumors invariably recur. Tumor associated macrophages (TAMs) have been proposed as a mechanism of resistance to anti-angiogenic therapy in preclinical models. To examine the role of TAMs in recurrent GBM, we analyzed autopsy specimens from patients with or without history of antiangiogenic therapy. Methods: We compared autopsy brain specimens from 17 recurrent GBM patients who received anti-angiogenic treatment and chemoradiation (AAT+) to 7 patients who received chemotherapy and/or radiotherapy without anti-angiogenic therapy, or no treatment (AAT-). TAMs were morphologically and phenotypically identified with flow cytometry and immunohistochemistry (IHC) with CD68, CD11b, CD14, and CD163 markers. All specimens were obtained from the Department of Pathology at Massachusetts General Hospital and clinical information gained through review of the patients’ records. Results: Using flow cytom...