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Neoadjuvant antiangiogenic therapy reveals contrasts in primary and metastatic tumor efficacy.

ABSTRACT: Thousands of cancer patients are currently in clinical trials evaluating antiangiogenic therapy in the neoadjuvant setting, which is the treatment of localized primary tumors prior to surgical intervention. The rationale is that shrinking a tumor will improve surgical outcomes and minimize growth of occult micrometastatic disease-thus delaying post-surgical recurrence and improving survival. But approved VEGF pathway inhibitors have not been tested in clinically relevant neoadjuvant models that compare pre- and post-surgical treatment effects. Using mouse models of breast, kidney, and melanoma metastasis, we demonstrate that primary tumor responses to neoadjuvant VEGFR TKI treatment do not consistently correlate with improved post-surgical survival, with survival worsened in certain settings. Similar negative effects did not extend to protein-based VEGF pathway inhibitors and could be reversed with altered dose, surgical timing, and treatment duration, or when VEGFR TKIs are combined with metronomic 'anti-metastatic' chemotherapy regimens. These studies represent the first attempt to recapitulate the complex clinical parameters of neoadjuvant therapy in mice and identify a novel tool to compare systemic antiangiogenic treatment effects on localized and disseminated disease.

SUBMITTER: Ebos JM

PROVIDER: S-EPMC4287975 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Neoadjuvant antiangiogenic therapy reveals contrasts in primary and metastatic tumor efficacy.

Ebos John M L JM Mastri Michalis M Lee Christina R CR Tracz Amanda A Hudson John M JM Attwood Kristopher K Cruz-Munoz William R WR Jedeszko Christopher C Burns Peter P Kerbel Robert S RS

EMBO molecular medicine 20141201 12

Thousands of cancer patients are currently in clinical trials evaluating antiangiogenic therapy in the neoadjuvant setting, which is the treatment of localized primary tumors prior to surgical intervention. The rationale is that shrinking a tumor will improve surgical outcomes and minimize growth of occult micrometastatic disease-thus delaying post-surgical recurrence and improving survival. But approved VEGF pathway inhibitors have not been tested in clinically relevant neoadjuvant models that ...[more]

PMID: 25361689

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Project description:ObjectivesEfforts to improve the clinical outcome for patients with localized high-risk prostate cancer have led to the development of neoadjuvant systemic therapies. We review the different modalities of neoadjuvant therapies for localized prostate cancer and highlight emerging treatment approaches including immunotherapy and targeted therapy.MethodsWe performed a PubMed search of clinical trials evaluating preoperative systemic therapies for treating high-risk prostate cancer published after 2000, and those studies with the highest clinical relevance to current treatment approaches were selected for review. The database at clinicaltrials.gov was queried for neoadjuvant studies in high-risk prostate cancer, and those evaluating novel targeted therapies and immunotherapies are spotlighted here.ResultsNeoadjuvant chemotherapy has become standard of care for treating some malignancies, including breast and bladder cancers. In prostate cancer, preoperative hormonal therapy or chemotherapy has failed to demonstrate improvements in overall survival. Nevertheless, the emergence of novel treatment modalities such as targeted small molecules and immunotherapy has spawned neoadjuvant clinical trials that provide a unique vantage from which to study mechanism of action and biological potency. Tissue-based biomarkers are being developed to elucidate the biological efficacy of these treatments. With targeted therapy, these can include phospho-proteomic signatures of target pathway activation and deactivation. With immunotherapies, including sipuleucel-T and ipilimumab, recruitment of immune cells to the tumor microenvironment can also be used as robust markers of a biological effect. Such studies can provide insight not only into mechanism of action for these therapies but can also provide paths forward to improving clinical efficacy like with rationally designed combinations and dose selection.ConclusionsThe use of neoadjuvant androgen-deprivation therapy and chemotherapy either singly or in combination before radical prostatectomy is generally safe and feasible while reducing prostate volume and tumor burden. However, pathologic complete response rates are low and no long-term survival benefit has been observed with the addition of neoadjuvant therapies over surgery alone at present, and therefore preoperative therapy is not the current standard of care in prostate cancer treatment.

Project description:To evaluate the consistency of tumor blood volume measurements and antiangiogenic therapy efficacy assessments with a low-molecular-weight gadolinium-based contrast agent (GBCA, gadodiamide) versus an iron oxide nanoparticle (ferumoxytol) in the presence or absence of a loading dose of contrast agent before perfusion magnetic resonance (MR) imaging (preload method).The protocol was approved by the institutional animal care and use committee. U87MG tumor cells were implanted intracerebrally in 13 rats. All 13 rats underwent 11.75-T MR imaging with gadodiamide (60 μL) 13 days after tumor implantation. The next day, nine rats underwent MR imaging with ferumoxytol (60 μL). Immediately after ferumoxytol imaging, six rats received bevacizumab (45 mg/kg). MR imaging was repeated 48 hours after bevacizumab treatment with gadodiamide and 72 hours after treatment with ferumoxytol. Each study included three consecutive dynamic susceptibility-weighted contrast material-enhanced (DSC) MR acquisitions, which were performed without preload, with single-dose preload, and with double-dose preload. Tumor relative cerebral blood volume (rCBV) was estimated from each DSC MR acquisition. Two-way repeated measures analysis of variance was performed to test for differences between groups with both contrast agents.DSC MR imaging with gadodiamide and without preload showed low rCBV (≤ 1.75) in nine of the 13 tumors; estimated rCBV increased progressively with both single- and double-dose preloads (P < .001). Conversely, rCBVs obtained with ferumoxytol were high (>1.75) and remained constant with all three acquisitions. The magnitude of rCBV decrease after bevacizumab administration was dependent on the dose of gadodiamide preload, whereas the magnitude of rCBV decrease with ferumoxytol was constant regardless of whether contrast agent preload was used.With GBCA, tumor rCBV can be underestimated without preload and becomes dose dependent with preload correction. Conversely, ferumoxytol provides consistent assessment of tumor rCBV and antiangiogenic therapy efficacy.

Project description:Patients with breast cancer (BC) undergoing neoadjuvant chemotherapy (NACT) may experience metastatic relapse despite achieving a pathologic complete response. We analyzed patients with BC before and after NACT for disseminated tumor cells (DTCs) in the bone marrow(BM); comprehensively characterized circulating tumor cells (CTCs), including stem cell-like CTCs (slCTCs), in blood to prove the effectiveness of treatment on these cells; and correlated these findings with response to therapy, progression-free survival (PFS), and overall survival (OS).CTCs (n?=?135) and slCTCs (n?=?91) before and after NACT were analyzed using the AdnaTest BreastCancer, AdnaTest TumorStemCell, and epithelial-mesenchymal transition (QIAGEN Hannover GmbH Germany). The expression of estrogen receptor, progesterone receptor, and the resistance marker excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1), nuclease were studied in separate single-plex reverse transcription polymerase chain reaction experiments. DTCs were evaluated in 142 patients before and 165 patients after NACT using the pan-cytokeratin antibody A45-B/B3 for immunocytochemistry.The positivity rates for DTCs, CTCs, and slCTCs were 27 %, 24 %, and 51 % before and 20 %, 8 %, and 20 % after NACT, respectively. Interestingly, 72 % of CTCs present after therapy were positive for ERCC1, and CTCs before (p?=?0.005) and after NACT (p?=?0.05) were significantly associated with the presence of slCTCs. Whereas no significant associations with clinical parameters were found for CTCs and slCTCs, DTCs were significantly associated with nodal status (p?=?0.03) and histology (0.046) before NACT and with the immunohistochemical subtype (p?=?0.02) after NACT. Univariable Cox regression analysis revealed that age (p?=?0.0065), tumor size before NACT (p?=?0.0473), nodal status after NACT (p?=?0.0137), and response to NACT (p?=?0.0136) were significantly correlated with PFS, whereas age (p?=?0.0162) and nodal status after NACT (p?=?0.0243) were significantly associated with OS. No significant correlations were found for DTCs or any CTCs before and after therapy with regard to PFS and OS.Although CTCs were eradicated more effectively than DTCs, CTCs detected after treatment seemed to be associated with tumor cells showing tumor stem cell characteristics as well as with resistant tumor cell populations that might indicate a worse outcome in the future. Thus, these patients might benefit from additional second-line treatment protocols including bisphosphonates for the eradication of DTCs.

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Neoadjuvant antiangiogenic therapy reveals contrasts in primary and metastatic tumor efficacy.

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Neoadjuvant antiangiogenic therapy reveals contrasts in primary and metastatic tumor efficacy.

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