April 2016, Vol. 5, No. 3
Prolonged Survival of a Patient with Relapsed, Metastatic, SPARC-Overexpressed Lung Adenocarcinoma Treated with Low-Dose nab-PaclitaxelLung Adenocarcinoma
Secreted protein acidic and rich in cysteine (SPARC), also known as osteonectin and BM-40, is a collagen-binding matricellular protein that is involved in the regulation of a number of biological functions, including assembly of the extracellular matrix and the activity of matrix metalloproteinases and growth factors.1,2 In cancer, increased levels of SPARC can result in enhanced cell migration and invasion,1 and high levels of SPARC have been shown to be associated with poor prognosis in several types of cancer, including gastric,3 pancreatic,4 breast,5,6 lung,7 and head and neck.8,9
SPARC binds to albumin with high affinity10 and has been shown to increase the flux of albumin into endothelial cells.11 The albumin-binding protein gp60 mediates transendothelial albumin transport by binding albumin and activating caveolin-1, which leads to the formation of caveolae and the transport of albumin to the interstitial space.12,13
nab-Paclitaxel (Abraxane) is a formulation of paclitaxel bound to human albumin that allows administration without Cremophor, thus avoiding Cremophor-induced toxicity.14 In clinical trials, nab-paclitaxel plus carboplatin versus paclitaxel plus carboplatin significantly improved overall response rate in patients with advanced non–small cell lung cancer,15 nab-paclitaxel plus gemcitabine versus gemcitabine alone significantly increased overall survival for patients with advanced pancreatic cancer,16 and nab-paclitaxel versus paclitaxel demonstrated significantly higher response rates and significantly longer time to tumor progression in patients with metastatic breast cancer.17
A preclinical study in xenograft tumor models that compared the antitumor activity of nab-paclitaxel with Cremophor-based paclitaxel demonstrated that nab-paclitaxel increased the transendothelial transport of paclitaxel via gp60/caveolar-mediated transport, suggesting that albumin may play a role in the increased tumor uptake and increased efficacy of nab-paclitaxel.18 It has been postulated that the transport of nab-paclitaxel into the tumor interstitium is facilitated through binding of albumin to SPARC,19 and there is clinical evidence to suggest that elevated levels of SPARC are associated with improved responses to nab-paclitaxel. For example, a retrospective study of 16 patients with head and neck cancer showed that response to nab-paclitaxel was higher for SPARC-positive patients than SPARC-negative patients,20 and a phase 1/2 trial of nab-paclitaxel plus gemcitabine in advanced pancreatic cancer showed that high levels of stromal SPARC correlated with improved survival.21 In the subsequently reported phase 3 MPACT trial, there was no correlation between tumor epithelial and stromal SPARC with overall survival. Also reported was the laboratory investigation in a SPARC knockout mouse model wherein nab-paclitaxel activity was unrelated to SPARC expression.22
Here I describe a case that demonstrates an association between SPARC expression and tumor response in a patient with metastatic lung adenocarcinoma treated with single-agent nab-paclitaxel.
A 54-year-old Caucasian female with a 25 pack-year history of cigarette smoking was admitted to Greenville Memorial Hospital in February 2008, presenting with pneumonia. Clinical follow-up and CT imaging led to the discovery of a 3.5 × 2.7-cm left lung mass with a 1.7-cm subcarinal node; a needle biopsy revealed a well- to moderately well-differentiated stage IIIA (T2 N2 M0) adenocarcinoma. The patient had a past medical history of rheumatoid arthritis and cervical spine degenerative joint disease. Beginning July 8, 2008, the patient received 6 weekly doses of carboplatin (AUC 2) plus paclitaxel (45 mg/m2) with concomitant weekly radiation to a total of 6000 cGy; chemoradiation was completed September 12, 2008. She subsequently received 2 cycles of consolidation therapy comprised of carboplatin (AUC 6) and paclitaxel (200 mg/m2) once every 3 weeks. Therapy was terminated after the patient developed pancytopenia with a platelet count of 16,000 and bone marrow hypoplasia.
The patient remained disease free until a symptomatic solitary central nervous system (CNS) metastasis was detected. The metastasis was resected September 10, 2010, and the patient underwent postoperative whole brain radiation therapy (3000 cGy in 10 fractions); there was no evidence of other disease activity.
Subsequent disease progression, characterized by new bilateral pulmonary nodularity and retroperitoneal lymphadenopathy, was detected by CT and PET imaging in January 2011. A wedge resection of a nodule from the right lung was conducted in February 2011 revealing a well- to moderately well-differentiated adenocarcinoma. Genomic and proteomic profiling showed that the nodule was KRAS mutated (G to T mutation of nucleotide 35 resulting in a glycine to valine substitution), epidermal growth factor receptor wild type, not HER2 amplified, and contained overexpressed levels of SPARC (90% staining by polyclonal antibody; 50% staining by monoclonal antibody), Topo1, Topo2A, vascular epidermal growth factor receptor 2, PTEN, and MGMT.
Single-agent nab-paclitaxel (100 mg/m2 on days 1, 8, and 15 every 28 days) was initiated in March 2011 and, after 3 cycles, a CT scan of the thorax (May 2011) showed stable pulmonary nodularity and no evidence of retroperitoneal lymphadenopathy. A CT scan of the thorax in August 2011 showed resolution of multiple pulmonary nodules with nonspecific pulmonary nodularity remaining at less than 5 mm. A CT scan performed in March 2012 showed no evidence of active disease; PET and CT imaging, performed in August 2012, showed no hypermetabolic activity and no evidence of active disease. The patient received 29 cycles of nab-paclitaxel and tolerated treatment well with minimal myelosuppression, no peripheral neuropathy, and preservation of performance status. In July 2013, the patient developed a cough, and a CT scan of the thorax showed evidence of small-volume, intrathoracic disease progression. A needle biopsy of the left lung revealed a well- to moderately well-differentiated adenocarcinoma that was negative for SPARC overexpression, negative for RRM1, and positive for Topo1.
The patient received 4 cycles of gemcitabine (100 mg/m2 on days 1 and 8 every 21 days) between July 9, 2013, and August 16, 2013. Following cycle 4, the patient had progressive dyspnea and a large pleural effusion with persistent hypoxemia until her death in December 2013.
Prolonged survival was observed in a patient with SPARC-overexpressed metastatic lung adenocarcinoma treated with single-agent nab-paclitaxel who had previously progressed after receiving paclitaxel plus carboplatin and radiation therapy for stage III disease. Treatment with nab-paclitaxel was well tolerated with minimal myelosuppression and no neuropathy. Disease control for 2.5 years is remarkable for a patient with a CNS metastasis and a tumor harboring the KRAS mutation, both of which are commonly associated with a grim prognosis.
Tumor levels of SPARC appeared to be associated with the patient’s response to nab-paclitaxel: tumor response and prolonged disease control were associated with high levels of SPARC, and resistance to nab-paclitaxel/disease progression was associated with a reduction in the expression of SPARC. There is contradictory evidence regarding the association of SPARC overexpression and response to nab-paclitaxel. SPARC overexpression was shown to be associated with response to nab-paclitaxel in patients with head and neck cancer20 and improved survival in patients with advanced pancreatic cancer treated with nab-paclitaxel and gemcitabine.21 However, in a phase 2 study of patients with locally advanced head and neck cancer treated with nab-paclitaxel, cetuximab, cisplatin, and 5-fluorouracil, there was an inverse relationship between SPARC expression in tumor cells and tumor response,22 and no clear association was observed between expression of SPARC and the efficacy of nab-paclitaxel in patients with metastatic breast cancer.23
Studies showing that SPARC overexpression is correlated with response to nab-paclitaxel are limited by small patient numbers. However, the association of SPARC overexpression with prolonged disease control, as demonstrated in patients with head and neck cancer and pancreatic cancer as well as the current case, suggests that SPARC could be used as a predictive biomarker of response to nab-paclitaxel. Unfortunately, the results of the more robust phase 3 MPACT trial failed to confirm SPARC expression and efficacy of nab-paclitaxel. Certainly consideration must be given to the differences in tumor type, profiling of primary versus metastatic disease, and, potentially, differences in SPARC assay methodology.24 Larger, prospectively designed studies are needed to evaluate the clinical utility of SPARC as a predictive biomarker.
This case report highlights the scientific and philosophic shift in oncology therapeutics toward personalized therapy by identifying and targeting oncologic drivers in an ever-mutating disease. Prescribing individualized therapies based on advanced diagnostics will become commonplace as genomic sequencing and high-throughput proteomic technologies are adopted as standard tools.
Conflict of Interest Statement
W. Larry Gluck has no conflicts of interest to disclose.
- Bornstein P, Sage EH. Matricellular proteins: extracellular modulators of cell function. Curr Opin Cell Biol. 2002;14:608-616.
- Bradshaw AD. Diverse biological functions of the SPARC family of proteins. Int J Biochem Cell Biol. 2012;44:480-488.
- Wang Z, Hao B, Yang Y, et al. Prognostic role of SPARC expression in gastric cancer: a meta-analysis. Arch Med Sci. 2014;10:863-869.
- Infante JR, Matsubayashi H, Sato N, et al. Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. J Clin Oncol. 2007;25:319-325.
- Azim HA Jr, Singhal S, Ignatiadis M, et al. Association between SPARC mRNA expression, prognosis and response to neoadjuvant chemotherapy in early breast cancer: a pooled in-silico analysis. PLoS One. 2013;8:e62451.
- Jones C, Mackay A, Grigoriadis A, et al. Expression profiling of purified normal human luminal and myoepithelial breast cells: identification of novel prognostic markers for breast cancer. Cancer Res. 2004;64:3037-3045.
- Koukourakis MI, Giatromanolaki A, Brekken RA, et al. Enhanced expression of SPARC/osteonectin in the tumor-associated stroma of non-small cell lung cancer is correlated with markers of hypoxia/acidity and with poor prognosis of patients. Cancer Res. 2003;63:5376-5380.
- Chin D, Boyle GM, Williams RM, et al. Novel markers for poor prognosis in head and neck cancer. Int J Cancer. 2005;113:789-797.
- Kato Y, Nagashima Y, Baba Y, et al. Expression of SPARC in tongue carcinoma of stage II is associated with poor prognosis: an immunohistochemical study of 86 cases. Int J Mol Med. 2005;16:263-268.
- Sage H, Johnson C, Bornstein P. Characterization of a novel serum albumin-binding glycoprotein secreted by endothelial cells in culture. J Biol Chem. 1984;259:3993-4007.
- Goldblum SE, Ding X, Funk SE, et al. SPARC (secreted protein acidic and rich in cysteine) regulates endothelial cell shape and barrier function. Proc Natl Acad Sci U S A. 1994;91:3448-3452.
- John TA, Vogel SM, Tiruppathi C, et al. Quantitative analysis of albumin uptake and transport in the rat microvessel endothelial monolayer. Am J Physiol Lung Cell Mol Physiol. 2003;284:L187-L196.
- Schubert W, Frank PG, Razani B, et al. Caveolae-deficient endothelial cells show defects in the uptake and transport of albumin in vivo. J Biol Chem. 2001;276:48619-48622.
- Viudez A, Ramirez N, Hernández-Garcia I, et al. Nab-paclitaxel: a flattering facelift. Crit Rev Oncol Hematol. 2014;92:166-180.
- Socinski MA, Bondarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012;30:2055-2062.
- Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691-1703.
- Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23:7794-7803.
- Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res. 2006;12:1317-1324.
- Hawkins MJ, Soon-Shiong P, Desai N. Protein nanoparticles as drug carriers in clinical medicine. Adv Drug Deliv Rev. 2008;60:876-885.
- Desai N, Trieu V, Damascelli B, et al. SPARC expression correlates with tumor response to albumin-bound paclitaxel in head and neck cancer patients. Transl Oncol. 2009;2:59-64.
- Von Hoff DD, Ramanathan RK, Borad MJ, et al. Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial. J Clin Oncol. 2011;29:4548-4554.
- Adkins D, Ley J, Trinkaus K, et al. A phase 2 trial of induction nab-paclitaxel and cetuximab given with cisplatin and 5-fluorouracil followed by concurrent cisplatin and radiation for locally advanced squamous cell carcinoma of the head and neck. Cancer. 2013;119:766-773.
- Schneeweiss A, Seitz J, Smetanay K, et al. Efficacy of nab-paclitaxel does not seem to be associated with SPARC expression in metastatic breast cancer. Anticancer Res. 2014;34:6609-6615.
- Hidalgo M, Plaza C, Musteanu M, et al. SPARC expression did not predict efficacy of nab-paclitaxel plus gemcitabine or gemcitabine alone for metastatic pancreatic cancer in an exploratory analysis of the phase III MPACT trial. Clin Cancer Res. 2015;21:4811-4818.
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