Caveolin-1 expression predicts efficacy of weekly nab-paclitaxel plus gemcitabine for metastatic breast cancer in the phase II clinical trial

Abstract

BackgroundNanoparticle albumin-bound (nab)-paclitaxel has better efficacy, safety profiles, and no need to use prophylactic steroids compared with solvent-based paclitaxel. We performed a single arm, phase II study to evaluate the efficacy and safety of weekly nab-paclitaxel and gemcitabine combination in patients with metastatic breast cancer (MBC) and explored role of tumor/stromal Caveolin-1 (Cav-1) as a predictive biomarker for the efficacy.MethodsNab-paclitaxel (125 mg/m2) and gemcitabine (800 mg/m2) were administered on days 1, 8, and 15 in a 4-week cycle. The primary end point was objective response rate (ORR). Secondary end points were progression free survival (PFS), overall survival (OS) and safety profile. Exploratory study included immunohistochemical detection of Cav-1.ResultsAmong 85 patients enrolled in the study, ORR was 52.4%. After a median follow-up of 17.2 months, median PFS was 7.9 months (95%CI, 6.6–9.2) and median OS was 25.8 months (95% CI, 20.4–31.1). The most common toxicities were neutropenia (75.0% for all grades; 45.2% for grade 3 or worse) and the most common non-hematologic toxicity was peripheral neuropathy (50.0% for all grades, 7.14% for grade 3 or worse). Higher tumor Cav-1 level and lower stromal Cav-1 level were significantly associated with longer PFS of nab-paclitaxel and gemcitabine.ConclusionsThe regimen had substantial antitumor activity and was well tolerated in MBC patients. Tumor/stromal Cav-1 level may be a good predictor for the efficacy of nab-paclitaxel and gemcitabine.Trial registrationNCT01550848. Registered 12 March 2012.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4936-y) contains supplementary material, which is available to authorized users.

Phase II trial of gemcitabine and nab‐paclitaxel in patients with recurrent Ewing sarcoma: A report from the National Pediatric Cancer Foundation

“…Because this regimen has toxicity but only limited activity, identification of predictive biomarkers would be quite helpful for patient selection. Previous studies suggested that expression of either SPARC or CAV‐1 in archival tumor samples may correlate with response to nab‐paclitaxel, 20‐22 which fits with the presumed method of drug entry into the tumor cell. However, not all studies confirm this association between SPARC expression and response to nab‐paclitaxel, 32 and it is possible that the predictive value of the marker may depend on tumor type or expression in stroma versus tumor cells 33 .…”

“…Based on the mechanism of nab-paclitaxel cell entry, protein expression of CAV-1 and SPARC are putative biomarkers for activity of this drug. [20][21][22] Similarly, human equilibrative nucleoside transporter-1…”

“…Based on the mechanism of nab-paclitaxel cell entry, protein expression of CAV-1 and SPARC are putative biomarkers for activity of this drug. [20][21][22] Similarly, human equilibrative nucleoside transporter-1 (hENT-1) facilitates transport of gemcitabine into cells, and its expression has correlated with gemcitabine response in patients with softtissue sarcoma. 23 We performed immunohistochemistry on the most recent archived tumor tissue available.…”

Paclitaxel’s Mechanistic and Clinical Effects on Breast Cancer

“…Cav-1 is the main component of plasma membrane invaginations (calveolae), and deregulation of tumor Cav-1 is highly implicated in BC. Moreover, loss of stromal Cav-1 plays an important role in disease recurrence and overall worse prognosis of BC patients [137]. Due to the presence of albumin, the binding of nab-PTX to gp60, an albumin receptor on endothelial cells, leads to the activation of caveolin-1 (Cav-1) and formation of calveolae [135].…”

Retrospective Cohort Study of Caveolin-1 Expression as Prognostic Factor in Unresectable Locally Advanced or Metastatic Pancreatic Cancer Patients

“…Most of these studies have been conducted in patients with breast and lung cancer, treatments which involve chemotherapy drugs that have to be internalized to be active. For breast cancer, nab-paclitaxel have been associated with highest intracellular concentration and activity whenever higher levels of Cav-1 expression were observed [ 24 , 25 ]. In particular, in metastatic breast cancer, Ricci et al evidenced that higher tumor and lower stromal Cav-1 levels were significantly correlated with a longer PFS of nab-paclitaxel and gemcitabine [ 26 ].…”