Identification of Markers of Taxane Sensitivity Using Proteomic and Genomic Analyses of Breast Tumors from Patients Receiving Neoadjuvant Paclitaxel and Radiation

Bauer, Joshua A.; Chakravarthy, A. Bapsi; Rosenbluth, Jennifer M.; Mi, Deming; Seeley, Erin H.; Granja-Ingram, Nara De Matos; Olivares, Maria G.; Kelley, Mark C.; Mayer, Ingrid A.; Meszoely, Ingrid M.; Means‐Powell, Julie; Johnson, Kimberly N.; Tsai, C. Jillian; Ayers, Gregory D.; Sanders, Melinda E.; Schneider, Robert J.; Formenti, Silvia C.; Caprioli, Richard M.; Pietenpol, Jennifer A.

doi:10.1158/1078-0432.ccr-09-1091

Cited by 162 publications

(120 citation statements)

References 48 publications

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“…In comparison, 13 patients (9.0%) discontinued paclitaxel due to drug-related AEs, frequently due to PMN (2.8%), increased alanine aminotransferase (2.8%), and PSN (2.1%). , which is similar to rates with single-agent paclitaxel in this setting [36]. Use of ixabepilone (or paclitaxel) after four courses of AC increased the pCR rate considerably.…”

Section: Safetysupporting

confidence: 72%

Neoadjuvant Doxorubicin/Cyclophosphamide Followed by Ixabepilone or Paclitaxel in Early Stage Breast Cancer and Evaluation of βIII-Tubulin Expression as a Predictive Marker

Saura

Tseng

Chan³

et al. 2013

The Oncologist

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Background. This randomized phase II trial was designed to compare the rate of pathologic complete response (pCR) induced by neoadjuvant cyclophosphamide plus doxorubicin (AC) followed by ixabepilone or paclitaxel in women with early stage breast cancer (BC). Expression of ␤III-tubulin as a predictive marker was also evaluated. Patients and Methods. Women with untreated, histologically confirmed primary invasive breast adenocarcinoma received four cycles of AC followed by 1:1 randomization to either ixabepilone 40 mg/m 2 (3-hour infusion) every 3 weeks for four cycles (n ϭ 148) or weekly paclitaxel 80 mg/m 2 (1-hour infusion) for 12 weeks (n ϭ 147). All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis prior to chemotherapy. ␤III-Tubulin expression was assessed using immunohistochemistry.Results. There was no significant difference in the rate of pCR in the ixabepilone treatment arm (24.3%; 90% confidence interval [CI], 18.6 -30.8) and the paclitaxel treatment arm (25.2%; 90% CI, 19.4 -31.7). ␤III-Tubulin-positive patients obtained higher pCR rates compared with ␤III-tubulin-negative patients in both treatment arms; however, ␤III-tubulin expression was not significantly associated with a differential response to ixabepilone or paclitaxel. The safety profiles of both regimens were generally similar, although neutropenia occurred more frequently in the ixabepilone arm (grade 3/4: 41.3% vs. 8.4%). The most common nonhematologic toxicity was peripheral neuropathy. Conclusions. Neoadjuvant treatment of early stage BC with AC followed by ixabepilone every 3 weeks or weekly paclitaxel was well tolerated with no significant difference in efficacy. Higher response rates were observed among ␤III-tubulin-positive patients. The Oncologist 2013;18:787-794 Implications for Practice: Neoadjuvant chemotherapy is a common practice in early breast cancer treatment. One of the most important challenges in the clinic is to identify biomarkers to select patients for different therapies and achieve better outcomes. ␤III-Tubulin expression is one of the well-established mechanisms of resistance to paclitaxel in vitro but limited clinical data exists regarding this issue. Single-agent neoadjuvant ixabepilone has previously demonstrated promising activity in invasive breast cancer, particularly in patients with high ␤III-tubulin mRNA levels. In this phase II trial, neoadjuvant cyclophosphamide plus doxorubicin, followed by a direct comparison to either ixabepilone or paclitaxel (1:1) in women with early stage breast cancer, was welltolerated with no significant difference in efficacy as measured by pathologic and clinical response. ␤III-Tubulin expression measured by immunohistochemistry was not significantly associated with preferential benefit from ixabepilone versus paclitaxel treatment, suggesting that ␤III-tubulin status defined by this technique should not be used for therapeutic decision-making in this patient population.Correspondence:CristinaSaura,M.D.

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Section: Safetysupporting

confidence: 72%

Neoadjuvant Doxorubicin/Cyclophosphamide Followed by Ixabepilone or Paclitaxel in Early Stage Breast Cancer and Evaluation of βIII-Tubulin Expression as a Predictive Marker

Saura

Tseng

Chan³

et al. 2013

The Oncologist

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“…Our 7 TNBC subtypes were characterized on the basis of gene ontologies and differential GE and subsequently labeled as follows: basal-like 1 (BL1); The highly proliferative nature of this subtype is further supported by the finding of high Ki-67 mRNA expression (MKI67) (Supplemental Figure 6) and nuclear Ki-67 staining as assessed by IHC analysis (BL1 + BL2 = 70% vs. other subtypes = 42%; P < 0.05) (Supplemental Figure 7). Enrichment of proliferation genes and increased Ki-67 expression in basal-like TNBC tumors suggest that this subtype would preferentially respond to antimitotic agents such as taxanes (paclitaxel or docetaxel) (21,22). This is indeed the case when comparing the percentage of patients achieving a pathologic complete response (pCR) in 42 TNBC patients treated with neoadjuvant taxane in 2 studies (22,23).…”

Section: Introductionmentioning

confidence: 96%

Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies

Lehmann¹,

Bauer²,

Chen³

et al. 2011

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Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted "driver" signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.

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“…In turn, m/z abundance patterns that discriminate different physiological or pathological conditions might be used as diagnostic or even prognostic markers (13,14). In recent years, MALDI IMS of proteins has been successfully applied to different cancer types from the brain (15), breast (16,17), kidney (18), prostate (19), and skin (20). Furthermore, the technique has been applied in the context of colon inflammation (21), embryonic development (22), Alzheimer's disease (23), and amyotrophic lateral sclerosis (24).…”

Section: Matrix-assisted Laser Desorption/ionization Imaging Mass Spementioning

confidence: 99%

Comprehensive Identification of Proteins from MALDI Imaging

Maier

Hahne

Gholami

et al. 2013

Molecular & Cellular Proteomics

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Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) is a powerful tool for the visualization of proteins in tissues and has demonstrated considerable diagnostic and prognostic value. One main challenge is that the molecular identity of such potential biomarkers mostly remains unknown. We introduce a generic method that removes this issue by systematically identifying the proteins embedded in the MALDI matrix using a combination of bottom-up and top-down proteomics. The analyses of ten human tissues lead to the identification of 1400 abundant and soluble proteins constituting the set of proteins detectable by MALDI IMS including >90% of all IMS biomarkers reported in the literature. Top-down analysis of the matrix proteome identified 124 mostly N-and C-terminally fragmented proteins indicating considerable protein processing activity in tissues. All protein identification data from this study as well as the IMS literature has been deposited into MaTisse, a new publically available database, which we anticipate will become a valuable resource for the IMS community. Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) 1 is an emerging technique that can be described as a multi-color molecular microscope as it allows visualizing the distribution of many molecules as mass to charge (m/z) signals in parallel in situ (1). Originally described some 15 years ago (2) the method has been successfully adapted to different analyte classes including small molecule drugs (3), metabolites (4), lipids (5), proteins (6), and peptides (7) using e.g. formalin fixed paraffin embedded (FFPE) as well as fresh frozen tissue (8). Because the tissue stays intact in the process, MALDI IMS is compatible with histochemistry (9) as well as immunohistochemistry and thus adds an additional dimension of molecular information to classical microscopy based tissue analysis (10). Imaging of proteins is appealing as it conceptually allows determining the localization and abundance of proteoforms (11) that naturally occur in the tissue under investigation including modifications such as phosphorylation, acetylation, or ubiquitination, protease mediated cleavage or truncation (12). Therefore a proteinous m/z species detected by MALDI IMS can be viewed as an in situ molecular probe of a particular biological process. In turn, m/z abundance patterns that discriminate different physiological or pathological conditions might be used as diagnostic or even prognostic markers (13,14). In recent years, MALDI IMS of proteins has been successfully applied to different cancer types from the brain (15), breast (16, 17), kidney (18), prostate (19), and skin (20). Furthermore, the technique has been applied in the context of colon inflammation (21), embryonic development (22), Alzheimer's disease (23), and amyotrophic lateral sclerosis (24). With a few notable exceptions (13, 14, 16 -18, 20, 24 -30), the identity of the proteins constituting the observed characteristic m/z patters has generally remained e...

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Identification of Markers of Taxane Sensitivity Using Proteomic and Genomic Analyses of Breast Tumors from Patients Receiving Neoadjuvant Paclitaxel and Radiation

Cited by 162 publications

References 48 publications

Neoadjuvant Doxorubicin/Cyclophosphamide Followed by Ixabepilone or Paclitaxel in Early Stage Breast Cancer and Evaluation of βIII-Tubulin Expression as a Predictive Marker

Neoadjuvant Doxorubicin/Cyclophosphamide Followed by Ixabepilone or Paclitaxel in Early Stage Breast Cancer and Evaluation of βIII-Tubulin Expression as a Predictive Marker

Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies

Comprehensive Identification of Proteins from MALDI Imaging

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