SPARC microenvironment signature (SMS) analysis of a phase II trial of neoadjuvant gemcitabine (G), epirubicin (E), and <i>nab</i>-paclitaxel (<i>nab</i>-P) in locally advanced breast cancer (LABC).

Yardley, DA; Daniel, Brooke R.; Inhorn, Roger C.; Vazquez, Elizabeth R.; Trieu, V.; Motamed, Kouros; Hwang, Lih Hwa; Rugo, HS; Desai, Neil

doi:10.1200/jco.2010.28.15_suppl.10574

Cited by 8 publications

(6 citation statements)

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“…81–83 SPARC expression noted in the stroma in pancreatic cancer but not in tumor cells has been associated with poor survival. 84–86 It has been noted that nanoparticle albumin (nab) paclitaxel had shown clinical antitumor activity in several cancer types that overexpressed SPARC.…”

Section: Desmoplasia In Tumor Microenvironment and Therapeutic Approamentioning

confidence: 99%

Orchestrating the Tumor Microenvironment to Improve Survival for Patients With Pancreatic Cancer

Whatcott

Han²,

Hoff³

2015

The Cancer Journal

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Pancreatic cancer is the fourth leading cause of cancer death in the United States. The microenvironment of pancreatic cancer could be one of the “perfect storms” that support the growth of a cancer. Indeed, pancreatic cancer may be the poster child of a problem with the microenvironment. In this article, we review the rationale and attempts to date on modifying or targeting structural proteins in the microenvironment including hyaluronan (HA) (in primary and metastases), collagen, and SPARC (secreted protein, acidic, and rich in cysteine). Indeed, working in this area has produced a regimen that improves survival for patients with advanced pancreatic cancer (nab-paclitaxel + gemcitabine). In addition, in initial clinical trials, PEGylated hyaluronidase appears promising. We also review a new approach that is different than targeting/destroying the microenvironment and that is orchestrating, reengineering, reprogramming, or normalizing the microenvironment (including normalizing structural proteins, normalizing an immunologically tumor-friendly environment to a less friendly environment, reversing epithelial-to-mesenchymal transition, and so on). We believe this will be most effectively done by agents that have global effects on transcription. There is initial evidence that this can be done by agents such as vitamin D derivatives and other new agents. There is no doubt these opportunities can now be tried in the clinic with hopefully beneficial effects.

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Section: Desmoplasia In Tumor Microenvironment and Therapeutic Approamentioning

confidence: 99%

Orchestrating the Tumor Microenvironment to Improve Survival for Patients With Pancreatic Cancer

Whatcott

Han²,

Hoff³

2015

The Cancer Journal

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“…Plasma samples are also being obtained at baseline and cycle 3 in order to characterize tumor-derived cell-free DNA using digital polymerase chain reaction or whole-exome sequencing. Secreted protein acidic and rich in cysteine (SPARC) has been hypothesized to be a potential predictive biomarker for nab -paclitaxel efficacy, and higher SPARC expression has been reported in TNBC [ 35 – 37 ]. However, clinical data associating SPARC status with treatment efficacy in breast cancer are equivocal [ 35 , 36 , 38 , 39 ].…”

Section: Methodsmentioning

confidence: 99%

Phase II/III weekly nab-paclitaxel plus gemcitabine or carboplatin versus gemcitabine/carboplatin as first-line treatment of patients with metastatic triple-negative breast cancer (the tnAcity study): study protocol for a randomized controlled trial

Yardley

Brufsky

Coleman

et al. 2015

Trials

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BackgroundTriple-negative breast cancer is an aggressive disease with unmet clinical needs. In a phase III study of patients with metastatic triple-negative breast cancer, first-line gemcitabine/carboplatin resulted in a median progression-free survival of 4.6 months. nab-paclitaxel-based regimens (with gemcitabine or carboplatin ± bevacizumab) also demonstrated efficacy and safety in first-line phase II trials of human epidermal growth factor receptor 2-negative metastatic breast cancer.Trial designIn this international, multicenter, open-label, randomized phase II/III trial, the efficacy and safety of first-line nab-paclitaxel with gemcitabine or with carboplatin will be compared with gemcitabine/carboplatin (control arm) for metastatic triple-negative breast cancer.MethodsIn the phase II portion, 240 patients with measurable metastatic triple-negative breast cancer and treatment-naive for metastatic disease will be randomized 1:1:1 (stratified by disease-free interval: ≤ 1 versus > 1 year) to nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2 plus carboplatin area under the curve 2 mg × min/mL, or gemcitabine 1000 mg/m2 plus carboplatin area under the curve 2 mg × min/mL, all given on days 1 and 8 of a 21-day cycle. Investigator-assessed progression-free survival (primary endpoint), overall response rate, overall survival, and safety will be assessed. A ranking algorithm of five efficacy and safety parameters will be used to pick the “winner” of the nab-paclitaxel regimens. In the phase III portion, 550 patients will be randomized 1:1 (stratified by disease-free interval: ≤ 1 versus > 1 year, and prior adjuvant/neoadjuvant taxane use) to the nab-paclitaxel combination arm selected from the phase II portion or to the control arm. Patients in phase II will not be part of the phase III population. The phase III primary endpoint is blinded, independently-assessed progression-free survival; secondary endpoints include blinded, independently-assessed overall response rate, overall survival, disease control rate, duration of response, and safety. Biomarker and circulating tumor-cell exploratory analyses and quality-of-life assessments will also be performed. A list of approving ethical bodies was provided in Additional file 1.DiscussionThe tnAcity trial aims to identify a new standard cytotoxic chemotherapy regimen for first-line treatment of metastatic triple-negative breast cancer.Trial registrationClinicalTrials.gov: NCT01881230. Date of registration: 17 June 2013.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-015-1101-7) contains supplementary material, which is available to authorized users.

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“… 36 , 37 While SPARC expression in peritumoral stroma seems to correlate with worse outcomes in early stage pancreatic cancer, 38 , 39 it is debatable whether it correlates to improved efficacy from nab-paclitaxel-based therapy. 40 – 43 …”

Section: Nab-paclitaxelmentioning

confidence: 99%

Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies

Chiorean¹,

Coveler²

2015

DDDT

139

113

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Pancreatic cancer is the fourth leading cause of cancer death in the US and is expected to become the second leading cause of cancer-related deaths in the next decade. Despite 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel significantly improving outcomes for metastatic cancer, refractory disease still poses significant challenges. Difficulties with early detection and the inherent chemo- and radio-resistant nature of this malignancy led to attempts to define the sequential biology of pancreatic cancer in order to improve survival outcomes. Pancreatic adenocarcinoma is characterized by several germline or acquired genetic mutations, the most common being KRAS (90%), CDK2NA (90%), TP53 (75%–90%), DPC4/SMAD4 (50%). In addition, the tumor microenvironment, chemoresistant cancer stem cells, and the desmoplastic stroma have been the target of some promising clinical investigations. Among the core pathways reproducibly shown to lead the development and progression of this disease, DNA repair, apoptosis, G1/S cell cycle transition, KRAS, Wnt, Notch, Hedgehog, TGF-beta, and other cell invasion pathways, have been the target of “precision therapeutics”. No single molecularly targeted therapeutic though has been uniformly successful, probably due to the tumor heterogeneity, but biomarker research is evolving and it hopes to select more patients likely to benefit. Recent reports note activity with immunotherapies such as CD40 agonists, CCR2 inhibitors, cancer vaccines, and novel combinations against the immunosuppressive tumor milieu are ongoing. While many obstacles still exist, clearly we are making progress in deciphering the heterogeneity within pancreatic cancers. Integrating conventional and immunological targeting will be the key to effective treatment of this deadly disease.

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SPARC microenvironment signature (SMS) analysis of a phase II trial of neoadjuvant gemcitabine (G), epirubicin (E), and nab-paclitaxel (nab-P) in locally advanced breast cancer (LABC).

Cited by 8 publications

References 0 publications

Orchestrating the Tumor Microenvironment to Improve Survival for Patients With Pancreatic Cancer

Orchestrating the Tumor Microenvironment to Improve Survival for Patients With Pancreatic Cancer

Phase II/III weekly nab-paclitaxel plus gemcitabine or carboplatin versus gemcitabine/carboplatin as first-line treatment of patients with metastatic triple-negative breast cancer (the tnAcity study): study protocol for a randomized controlled trial

Pancreatic cancer: optimizing treatment options, new, and emerging targeted therapies

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