Conventional Taxanes Research Articles

Anticancer regimens containing third generation taxanes SB-T-121605 and SB-T-121606 are highly effective in resistant ovarian carcinoma model.

Taxanes are widely used in the treatment of ovarian carcinomas. One of the main problems with conventional taxanes is the risk of development of multidrug resistance. New-generation synthetic experimental taxoids (Stony Brook Taxanes; SB-T) have shown promising effects against various resistant tumor models. The aim of our study was to compare the in vitro efficacy, intracellular content, and in vivo antitumor effect of clinically used paclitaxel (PTX) and SB-Ts from the previously tested second (SB-T-1214, SB-T-1216) and the newly synthesized third (SB-T-121402, SB-T-121605, and SB-T-121606) generation in PTX resistant ovarian carcinoma cells NCI/ADR-RES. The efficacy of the new SB-Ts was up to 50-times higher compared to PTX in NCI/ADR-RES cells in vitro. SB-T-121605 and SB-T-121606 induced cell cycle arrest in the G2/M phase much more effectively and their intracellular content was 10-15-times higher, when compared to PTX. Incorporation of SB-T-121605 and SB-T-121606 into therapeutic regimens containing PTX were effective in suppressing tumor growth in vivo in NCI/ADR-RES based mice xenografts at small doses (≤3mg/kg), where their adverse effects were eliminated. In conclusion, new SB-T-121605 and SB-T-121606 analogs are promising candidates for the next phase of preclinical testing of their combination therapy with conventional taxanes in resistant ovarian carcinomas.

Efficacy and safety of nanoparticle-albumin-bound paclitaxel compared with conventional taxanes in women with breast cancer: a systematic review and meta-analysis

Long-term benefit of nanoparticle-albumin-bound paclitaxel (Nab-P) over conventional taxanes in breast cancer patients is still controversial. We conducted a systematic review of studies to identify the optimal taxanes for selection in clinical practice. We enrolled studies if they enrolled adults (age ≥18) with breast cancer, compared Nab-P (at any dose) to conventional paclitaxel or docetaxel, provided information on survival data, the response rate, or adverse events, were randomized controlled trials, case-control studies, or cohort studies, and were published in English (including those published online, ahead of the print publication). Cochrane Collaboration tool and Newcastle-Ottawa scale were used for bias-risk assessment. Grading of recommendations assessment, development, and evaluation approach were adopted for the quality of evidence evaluation. The outcomes included the overall response rate, pathological complete response rate, progression-free survival, overall survival, allergic reaction, leukopenia, neutropenia, and sensory neuropathy. A total of 20 eligible clinical studies comprising 11,046 patients were included in the analysis. No significant publication bias was observed based on a visual inspection of the funnel plots for progressionfree survival (PFS), and overall survival (OS). Compared to the conventional taxanes group (n=2,743), the Nab-P group (n=1,680) had a significantly higher ORR (RR =1.21, 95% CI: 1.07-1.37; P=0.003) and pCR (RR =1.33, 95% CI: 1.17-1.51; P<0.001). The Nab-P group also had a lower risk of disease progression and death than the conventional taxanes group (HR =0.89, P=0.269). Additionally, the Nab-P group had fewer treatment-related allergic reactions (RR =0.74, 95% CI: 0.59-0.93; P=0.009) and less grade ≥4 neutropenia (RR =0.39, 95% CI: 0.20-0.77; P=0.007) than the conventional taxanes group. The incidence of any-grade of neutropenia and sensory neuropathy were significantly higher in the Nab-P group than the conventional taxanes group (P=0.009 and P<0.001, respectively). The Nab-P in all stages of breast cancer patients had significantly better efficacy and tolerance than the conventional taxanes. Moreover, preventive strategies for reducing the incidence of Nab-P induced sensory neuropathy should be explored in future studies.

The efficacy and safety of apatinib combined with paclitaxel and carboplatin dose-dense regimen in neoadjuvant therapy for locally advanced triple-negative breast cancer.

e12602 Background: Triple negative breast cancer (TNBC) has the traits of early onset, high malignancy and no effective molecular targets to act on, neoadjuvant chemotherapy is recommended as the preferred treatment for locally advanced TNBC with highly recurrence risk. The addition of platinum-based agents to conventional taxanes regimens in locally advanced TNBC can significantly improve pathological complete response (pCR) rate. Anti-angiogenic drugs are currently one of the few targeted therapies that have achieved efficacy in TNBC. Apatinib, an inhibitor of VEGFR2, shows significant antitumor activity in the patients with breast cancer. Methods: Pathologically confirmed TNBC patients with clinical stage I-IIIC (per AJCC 8th ed) with no previous surgery or radio-chemotherapy treatment were enrolled in our center from September 2018 to June 2020. Enrolled patients received 4-8 neoadjuvant treatment cycles of apatinib 250mg per day + paclitaxel 175mg/m2 d1 + carboplatin AUC = 4 d2 q14d (Apa+TC), followed by sequential surgery. Enrolled patients who underwent surgery were matched with TNBC patients received paclitaxel and carboplatin intense regimen (TC) contemporarily in our center by propensity score matching (PSM). pCR in breast and axilla (ie. ypT0/Tis ypN0) was the primary endpoint. Objective response rate (ORR), disease control rate (DCR), event-free survival (EFS), overall survival (OS) and adverse events (AEs) are secondary endpoints. Results: 25 locally advanced TNBC patients were enrolled for neoadjuvant therapy of Apa+TC. In radiological evaluation, 2 patients achieved CR, 20 patients achieved PR, 3 patients achieved SD, which indicated an ORR of 88% and a DCR of 100%. 23 of 25 enrolled patients underwent surgery, with a pCR rate of 60.87% (95%CI: 38.54%-80.29%). 69 patients who were treated by TC before surgery were matched by PSM based on baseline stage T and stage N features. A significant higher pCR rate was achieved in Apa+TC arm compared with TC alone (60.87% vs. 30.43%, respectively, P = 0.009). Similar incidence of AEs was observed between two arms. The main AEs were hematologic toxicities fatigue, digestive canal symptoms, transaminase elevation and peripheral neurotoxicity in Apa+TC arm. Grade III-IV AEs included granulocytopia (14/25), thrombocytopenia (4/25), anaemia (3/25), fatigue (1/25), hypertension (1/25) and arrhythmia (1/25). Meanwhile, apatinib-related AEs, including hypertension, proteinuria, and hand-and-foot syndrome, were mild. Due to the limited time, the survival follow-up is still in progress. Conclusions: Apatinib combined with paclitaxel and carboplatin intensive regimen achieved a better efficacy and manageable adverse events in neoadjuvant chemotherapy for locally advanced TNBC, which might be a promising strategy in the treatment of locally advanced TNBC. Clinical trial information: NCT03735082.

The Role of TRIP6, ABCC3 and CPS1 Expression in Resistance of Ovarian Cancer to Taxanes.

The main problem precluding successful therapy with conventional taxanes is de novo or acquired resistance to taxanes. Therefore, novel experimental taxane derivatives (Stony Brook taxanes; SB-Ts) are synthesized and tested as potential drugs against resistant solid tumors. Recently, we reported alterations in ABCC3, CPS1, and TRIP6 gene expression in a breast cancer cell line resistant to paclitaxel. The present study aimed to investigate gene expression changes of these three candidate molecules in the highly resistant ovarian carcinoma cells in vitro and corresponding in vivo models treated with paclitaxel and new experimental Stony Brook taxanes of the third generation (SB-T-121605 and SB-T-121606). We also addressed their prognostic meaning in ovarian carcinoma patients treated with taxanes. We estimated and observed changes in mRNA and protein profiles of ABCC3, CPS1, and TRIP6 in resistant and sensitive ovarian cancer cells and after the treatment of resistant ovarian cancer models with paclitaxel and Stony Brook taxanes in vitro and in vivo. Combining Stony Brook taxanes with paclitaxel caused downregulation of CPS1 in the paclitaxel-resistant mouse xenograft tumor model in vivo. Moreover, CPS1 overexpression seems to play a role of a prognostic biomarker of epithelial ovarian carcinoma patients’ poor survival. ABCC3 was overexpressed in EOC tumors, but after the treatment with taxanes, its up-regulation disappeared. Based on our results, we can suggest ABCC3 and CPS1 for further investigations as potential therapeutic targets in human cancers.

Recent Clinical Developments of Nanomediated Drug Delivery Systems of Taxanes for the Treatment of Cancer.

Conventional taxanes are used as cornerstone of the chemotherapeutical treatment for a variety of malignancies. Nevertheless, a large proportion of patients do not benefit from their treatment while they do suffer from severe adverse events related to the solvent or to the active compound. Cremophor EL and polysorbate 80 free formulations, conjugates, oral formulations and different types of drug delivery systems are some examples of the several attempts to improve the treatment with taxanes. In this review article, we discuss recent clinical developments of nanomediated drug delivery systems of taxanes for the treatment of cancer. Targeting mechanisms of drug delivery systems and characteristics of the most commonly used taxane-containing drug delivery systems in the clinical setting will be discussed in this review.

Is nab-paclitaxel better than conventional taxanes as neoadjuvant therapy for breast cancer? A meta-analysis.

ObjectiveThis study compared the efficacy and safety of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with conventional taxanes as neoadjuvant chemotherapy for breast cancer.MethodsWe searched the literature using PubMed, the Cochrane Library, and Web of Science from their inception to December 15, 2019 based on predetermined inclusion and exclusion criteria. The relevant studies compared pathologic complete response (pCR) and adverse event rates.ResultsThe meta-analysis included five studies and 2335 patients. Compared with conventional taxanes, neoadjuvant chemotherapy with nab-paclitaxel was associated with a higher pCR rate (odds ratio [OR] = 1.39, 95% confidence interval [CI] = 1.16–1.67), especially among patients with triple-negative breast cancer or Ki67 indices of >20%. Pooled outcomes also revealed better event-free survival in the nab-paclitaxel group (hazard ratio = 0.69, 95% CI = 0.57–0.85). However, all-grade (OR = 2.17, 95% CI = 1.38–3.40) and grade ≥3 peripheral sensory neuropathy (OR = 3.92, 95% CI = 2.44–6.28) were more frequent in the nab-paclitaxel group.ConclusionsThis meta-analysis implied that nab-paclitaxel more effectively improved pCR than conventional taxanes. Nab-paclitaxel may have greater benefits in patients with triple-negative breast cancer. However, additional attention is required for the early diagnosis and management of peripheral sensory neuropathy.

Taxanes – The Backbone of Medical Oncology

AbstractDrug development in oncology has witnessed a revolutionary growth from its humble beginning with nitrogen mustard in 1940 to immunotherapy in 1986 (Interferon alpha). The arsenal of cytotoxics is ever increasing, contributing to better survival outcomes and improved quality of life. Over the years, many cytotoxics have fallen out of favor too, due to its side effects and availability of drugs with better efficacy and toxicity profile. Taxane, a microtubule stabilizing agent extracted from the poisonous Yew tree, was discovered in 1964 and came into clinical use in 1992 with its approval for ovarian cancer. This group has grown into a cornerstone of many treatment protocols, spanning multiple tumor types. This review discusses in brief the salient features of cytotoxic agents in this drug group, its history, physico-chemical properties, mechanism of action, pharmacodynamics, and pharmacokinetics. Though the benefits of taxanes are well understood, there are unique problems associated with the use of taxanes and there is an expanding literature on taxane resistance. We briefly look at the resistance mechanisms. There have been significant efforts to circumvent the problems related to conventional taxanes, with an attempt at creating newer carrier molecules and adjunct drugs with taxanes, which is slowly gaining traction in clinical practice.

The mesenchymal transition subtype more responsive to dose dense taxane chemotherapy combined with carboplatin than to conventional taxane and carboplatin chemotherapy in high grade serous ovarian carcinoma: A survey of Japanese Gynecologic Oncology Group study (JGOG3016A1)

ObjectiveRecently, we established new histopathological subtypes of high-grade serous ovarian cancer (HGSOC) that include the mesenchymal transition (MT) type, the immune reactive (IR) type, the solid and proliferative (SP) type and the papillo-glandular (PG) type. Furthermore, we identified that the mesenchymal transcriptome subtype might be sensitive to taxane. We investigated whether these different histopathological subtypes of HGSOC require individualized chemotherapy for optimal treatment. MethodsWe conducted the Japanese Gynecologic Oncology Group (JGOG) 3016A1 study, wherein we collected hematoxylin and eosin slides (total n = 201) and performed a histopathological analysis of patients with HGSOC registered in the JGOG3016 study, which compared the efficacy of conventional paclitaxel and carboplatin (TC) and dose-dense TC (ddTC). We analyzed the differences in progression-free survival (PFS) and overall survival (OS) among the four histopathological subtypes. We then compared the PFS between the TC group and the ddTC group for each histopathological subtype. ResultsThere were significant differences in both PFS and OS among the four histopathological subtypes (p = 0.001 and p < 0.001, respectively). Overall, the MT subtype had the shortest PFS (median 1.4 y) and OS (median 3.6 y). In addition, the MT subtype had a longer PFS in the ddTC group (median 1.8 y) than in the TC group (median 1.2 y) (p = 0.01). Conversely, the other types had no significant difference in PFS when the two regimens were compared. ConclusionsThe MT type of HGSOC is sensitive to taxane; therefore, the ddTC regimen is recommended for this histopathological subtype.

Efficacy and safety of nanoparticle albumin-bound paclitaxel as neoadjuvant chemotherapy in HER2-negative breast cancer.

Nanoparticle albumin-bound paclitaxel (Nab-PTX) is a form of paclitaxel bound to albumin nanoparticles and is used widely in a neoadjuvant setting for patients with breast cancer. We conducted a retrospective study to compare the efficacy and safety of Nab-PTX to PTX as neoadjuvant chemotherapy for patients with operable HER2-negative breast cancer. In total, 50 patients were enrolled. Nab-PTX was administered in the study group, and PTX was administered in the control group. The clinical response and safety profile were recorded. The expression of secreted protein acidic rich in cysteine (SPARC) in tumor tissue was examined. The efficacy and safety analyses were computed using SPSS statistical software. Multiple logistic regression analysis was performed to evaluate the exploratory variables (age, stage, estrogen receptor, partial response, and SPARC expression) for the pathological complete response (pCR), and Fisher's exact test was performed to evaluate the relationship between SPARC and pCR. Both groups of patients achieved a good clinical response. The pCR rate for the Nab-PTX regimen was significantly higher than that for the PTX regimen. The most common adverse events were neutropenia, peripheral sensory neuropathy, arthralgia, and myalgia. In 68% of cases in the Nab-PTX group, high SPARC expression was observed. As neoadjuvant therapy, the Nab-PTX regimen has advantages over conventional taxane regimen in patients with HER2-negative breast cancer. With this regimen, a high pCR rate was achieved with a good safety profile.

Role of nab-paclitaxel in metastatic breast cancer: a meta-analysis of randomized clinical trials.

Whether nab-paclitaxel and conventional taxanes are equally effective for metastatic breast cancer (MBC) remains unclear. We conducted meta-analysis of trials that compared nab-paclitaxel-based chemotherapy with solvent-based paclitaxel (sb-paclitaxel) and docetaxel-based chemotherapy. A literature search was performed to identify articles that compared nab-paclitaxel-based chemotherapy with sb-paclitaxel or docetaxel-based chemotherapy for MBC. Four randomized controlled trials (1,506 patients) were identified from 1,268 reports. We detected equivalent overall response, overall survival, and survival probability (one-year, two-year). Grade 3 to 4 hematological and non-hematological toxicities were also comparable except that sensory neuropathy was more prominent for nab-paclitaxel-based chemotherapy (16.9% vs. 10%, odds ratio = 1.89, 95% confidence interval = 1.36–2.61, P < 0.001). No significant publication bias was detected. Consistent results stratified by treatment arm, study phase, treatment line, and study location were observed, except that overall response rate to nab-paclitaxel-based chemotherapy was significantly higher in the subgroup of randomized phase II trials, non-first-line treatment, and East Asian population. This meta-analysis failed to demonstrate advantages of nab-paclitaxel compared with sb-paclitaxel and docetaxel in patients with MBC. The newer agent was associated with increased sensory neuropathy, equivalent survival, and possibly increased overall response for some specific patients.

Is the mesenchymal transition subtype more responsive to dose dense taxane chemotherapy combined with carboplatin (ddTC) than to conventional taxane and carboplatin chemotherapy (TC) in high grade serous ovarian carcinoma? A survey of Japanese Gynecology Oncology Group study (JGOG3016A1).

5510 Background: High-grade serous ovarian cancer (HSOC) was divided into four transcriptome subtypes (i.e. Mesenchymal, Immunoreactive, Proliferative, and Differentiated). We established a new pathological classification based on these transcriptome subtypes: Mesenchymal Transition (MT) type, Immune Reactive (IR) type, Solid and Proliferative (SP) type and Papillo-Glandular (PG) type (PMID: 26993207). The MT type has the worst prognosis. We discovered the Mesenchymal transcriptome subtype might be sensitive to taxane chemotherapy. Therefore, we hypothesized that the MT type, which represents the Mesenchymal transcriptome subtype, may respond better to dose dense taxane combined with carboplatin (ddTC) rather than to conventional taxane and carboplatin (TC). Methods: We collected 207 HSOC slides registered in the Japanese Gynecology Oncology Group 3016 (JGOG3016) study. Two of the authors, R.M. and I.K., classified the samples into the four pathological subtypes (n=201). We categorized the patients into two groups based on the treatment they received: ddTC (n=95) or TC (n=106). Progression free survival (PFS) was compared between the two groups for each pathological subtype. Results: Among the MT patients, the ddTC group had a significantly better PFS than the TC group (n= 30 vs 42, median survival: 1.8 vs 1.2 years, p=0.01). Among the SP patients, the ddTC group had better PFS than the TC group, even though the difference was not statistically significant (n=22 vs 27, median survival: 3.2 vs 1.4 years, p=0.08). In contrast, among the IR patients, the two groups showed no significant difference in PFS (n=16 vs 16, median survival: 5.2 vs 5.8 years, p=0.64). The PG patients also showed no significant difference in PFS between the two groups (n=27 vs 21, median survival: 1.5 and 1.7 years, p=0.64). Conclusions: The HSOC of MT type is more responsive to ddTC than to TC. This new pathological classification reflecting HSOC transcriptome subtypes leads to individualization of chemotherapy treatments.

Abstract P5-16-29: Nanoparticle albumin-bound paclitaxel as neoadjuvant chemotherapy of breast cancer: A meta-analysis

Abstract Background: Nanoparticle albumin-bound paclitaxel (nab-Paclitaxel), a novel solvent-free taxane-based regimen, was hypothesized to have enhanced drug transport to tumors, shorter infusion schedules and no need for premedication. The value of nab-Paclitaxel in neoadjuvant systemic therapy (NST) for breast cancer remains uncertain. We performed a meta-analysis to assess efficacy and toxicity of nab-Paclitaxel compared to conventional taxane regimens (paclitaxel, docetaxel) within randomized clinical trials. Methods: A systematic search was performed using the medical subject heading (MeSH) terms ''breast neoplasms'', as well as (1) breast cancer; AND (2) nab-Paclitaxel OR nanoparticle paclitaxel; AND (3) neoadjuvant OR preoperative OR primary systemic in both Pubmed databases and proceedings of oncologic meetings including ASCO, ESMO and SABCS. Pooled rates of pathological complete response(pCR), odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed-effect or random-effect model to determine the effect of neoadjuvant nab-paclitaxel. Results: Twenty-one studies with 2357 patients were included, 3 of which (GeparSepto[1], ETNA[2], Showa trial[3]) were randomized clinical trials. The aggregate pCR rate (ypT0/is ypN0) was 32% (95% CI 25-38%) in unselected breast cancer patients and was 14%(95% CI 11-17%), 41%(95% CI 38-45%), 54%(95% CI 43-66%) in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-), triple negative breast cancer(TNBC), HER2+ patients, respectively. Within the HER2+ population, pCR rate was 61%(95% CI 47-74%) for HR- and 40%(95% CI 28-52%) for HR+ tumors. Regarding randomized clinical trials, the probability of achieving pCR was significantly higher in the nab-paclitaxel group than in the conventional taxanes group (OR=1.383, 95%CI 1.141-1.676, p=0.001). A funnel plot of the effect size for each randomized trial against the precision showed no asymmetry, which indicating no potential publication bias. In the safety analysis (GeparSepto[1], ETNA[2]), hematological toxic effects were generally equivalent in nab-paclitaxel and paclitaxel group. For non-hematological toxic effects, all grades and grade≥ 3 peripheral sensory neuropathy occurred more frequently with nab-paclitaxel compared to paclitaxel (all grades, OR=2.090, 95%CI 1.016-4.302, p=0.045; grade≥ 3, OR=3.766, 95%CI 2.324-6.100, p&amp;lt;0.001). Hypersensitivity was more common with paclitaxel than nab-paclitaxel at any grade and grade≥ 3. Other non-hematological toxic effects did not significantly differ between two groups. Conclusion: nab-Paclitaxel is an effective antitumor drug in NST of breast cancer, especially for TNBC and HER2+ tumors, in terms of pCR. Exchange of nab-Paclitaxel for conventional taxanes could significantly improve pCR rate with reasonable toxicities. Clinical trial information: 1.Lancet Oncol.2016,17:345-56.; 2.J Clin Oncol.2016,34(suppl; abstract 502).; 3.J Clin Oncol.2015,33(suppl; abstract 136). Citation Format: Zong Y, Wu J, Shen K. Nanoparticle albumin-bound paclitaxel as neoadjuvant chemotherapy of breast cancer: A meta-analysis [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-29.

Nanoparticle albumin-bound paclitaxel as neoadjuvant chemotherapy of breast cancer: a systematic review and meta-analysis.

BackgroundThe value of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in neoadjuvant systemic therapy for breast cancer remains uncertain.MethodsBoth electronic databases and proceedings of oncologic meetings were included in systematic literature search. Pooled rates of pathological complete response (pCR), odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed-effect or random-effect model to determine the effect of neoadjuvant nab-paclitaxel.ResultsTwenty-one studies with 2357 patients were included, 3 of which were randomized clinical trials. The aggregate pCR(ypT0/is ypN0) rate was 32% (95% CI 25-38%) in unselected breast cancer patients and variated in different subtypes. Within randomized clinical trials, the probability of achieving pCR was significantly higher in the nab-paclitaxel group than in the conventional taxanes group (OR = 1.383, 95%CI 1.141-1.676, p = 0.001). For non-hematological toxic effect, any grade and grade 3-4 peripheral sensory neuropathy occurred more frequently with nab-paclitaxel compared to paclitaxel (any grade, OR = 2.090, 95%CI 1.016-4.302, p = 0.045; grade3-4, OR = 3.766, 95%CI 2.324-6.100, p < 0.001). Hypersensitivity was more common with paclitaxel than nab-paclitaxel at any grade and grade 3-4.Conclusionnab-paclitaxel is an effective cytotoxic drug in neoadjuvant treatment of breast cancer, especially for aggressive tumors in terms of pCR. Exchange of nab-paclitaxel for conventional taxanes could significantly improve pCR rate with reasonable toxicities.

Abstract PR17: Characterization of ascites and tumor-derived ovarian cancer stem-like cells.

Abstract Intratumoral heterogeneity of high grade serous ovarian cancer (HGS-OvCa) provides a major challenge for current treatments. The non-responsiveness of ovarian cancer stem-like cells to current therapies is likely to be a reason for relapse and treatment failure. Here, we studied the ovarian cancer stem cell hypothesis and treatment failure with a population of 13 well characterized primary HGS-OvCa cell lines, 7 commonly available cell lines (Caov-3, Caov-4, TYK-nu, TYK-nu CP-r, NIHOVCAR3, OVCAR8, and SKOV3) and 29 tissue samples originated from patients with stage III and IV HGS-OvCa. Study patients were treated either with primary surgery followed by adjuvant platinum and taxane based chemotherapy (6 chemotherapy cycles, naiive samples) or neoadjuvant chemotherapy (3 cycles of platinum and taxane) followed by interval debulking surgery and 3 to 6 additional chemotherapy cycles (interval samples). Tissue samples, commonly available cell lines and primary cell lines isolated from tumor or ascites were thoroughly characterized with a panel of nine stemness associated markers: ALDH1A1, Cip2A (KIAA1524), c-Myc, Lin28A, Nanog, POU1F5B (Oct-4A), Oct3/4, Sox-2, CD133 and BMI-1. The expression of these markers was studied in two cell culture conditions; spheroidal, which is believed to promote stemness, and adherent. Additionally, we explored the effect of platinum and taxane based chemotherapy on stemness marker expression profile and furthermore the association of stemness markers with survival. The comparison of spheroidal and adherent cell growth conditions indicated that spheroidal culture conditions induce the expression of stem cell markers specifically in cultured primary HGS-OvCa cell lines. Quantitative RT-PCR data analysis showed elevated levels of a number of genes, such as ALDH1A1 (p=0.042), Cip2A (p=0.005), Oct4A (p=0.021), Sox-2 (p=0.019) and BMI-1 (p=0.003). Based on clustering analysis with primary and commonly used HGS-OvCa cell lines and tissue samples, primary cell lines and tissue samples expressed more stemness markers than commonly available cell lines. Spheroidal cells were more resistant to platinum and taxane chemotherapy than adherently grown cells and clustered closer to tissue samples suggesting stemness marker expression profile similarity between primary spheroidal cells and tissues. Platinum and taxane chemotherapy increased the expression of several stemness associated markers, most prominently ALDH1A1, in interval samples as compared to naive samples. Importantly, strong immunohistochemical ALDH1A1 staining was significantly associated with short platinum free survival (p=0.027). We further validated the expression of stemness markers in an independent ovarian cancer cohort containing 144 primary tumor samples from HGS-OvCa patients. The expression of eight stemness marker genes stratified patient samples into two clusters with distinct stem cell marker expression profiles. ALDH1A1, Cip2A, c-Myc, Lin28A, Nanog, Oct3/4, Sox-2, CD133 and BMI-1 were clustered together and were associated with shorter overall survival (log-rank test p=0.047). In conclusion, we have associated spheroidal cell growth conditions with tissue and stem cell -like profiles. Our results indicate that ALDH1A1 is one of the strongest markers of stemness in HGS-OvCa, and stem cell-like phenotype is enriched in interval samples as compared to naiive samples. Our results imply that conventional platinum taxane chemotherapy may enrich the population of stem-like cells and thus contribute to treatment failure. This abstract is also presented as Poster B65. Citation Format: Katja Kaipio, Ping Chen, Kaisa Huhtinen, Piia Mikkonen, Paivi Ostling, John Patrick Mpindi, Laura Lehtinen, Pia Roering, Taina Korpela, Krister Wennerberg, Bhagwan Yadav, Tero Aittokallio, Evgeny Kulesskiy, Johanna Hynninen, Annika Auranen, Seija Grénman, Sampsa Hautaniemi, Olli Carpén. Characterization of ascites and tumor-derived ovarian cancer stem-like cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr PR17.

Antitumor activity of Cetuximab in combination with Ixabepilone on triple negative breast cancer stem cells.

BackgroundDeveloping novel strategies against treatment-resistant triple negative breast cancer (TNBC) cells remains a significant challenge. The ErbB family, including epidermal growth factor receptor (EGFR), plays key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSC) which are believed to be responsible for tumor initiation and maintenance. Ixabepilone is a new generation microtubule-stabilizing agent, which has been expected to be more efficacious than conventional taxanes. Here we aim to investigate whether the EGFR monoclonal antibody Cetuximab, in combination with Ixabepilone, is more effective in eliminating CSC populations compared to chemotherapy alone in TNBC.MethodsRepresentative TNBC cell lines (MDA-MB-231 and SUM159) were used to evaluate breast CSC populations. We used fluorescence-activated cell sorter analysis (CD44+ and CD24-/low, or Aldefluor+) and a self-renewal assay called mammosphere formation efficiency (MSFE) to measure CSC population size after treatment with Cetuximab, or Cetuximab plus Ixabepilone in vitro.ResultsAlthough there was no significant decrease in cell viability, Cetuximab reduced MSFE and the CSC population in breast cancer cells in vitro and in vivo through inhibition of autophagy. Also, SUM159 and MDA-MB-231 orthotopic tumors demonstrated partial response to Centuximab or Ixabepilone monotherapy; however, the effect of the combination treatment was significant only in SUM159 tumors (p <0.0001), when compared to Ixabepilone alone.ConclusionsOverall, our findings demonstrate that EGFR-targeted therapy by Cetuximab effectively reduces the CSC population in TNBC tumors. However, combination therapy with Ixabepilone may be effective only in a small subset of TNBCs, warranting further investigation of alternative approaches to target multiple pathways for TNBC treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0662-4) contains supplementary material, which is available to authorized users.

Incidence and risk of peripheral neuropathy with nab-paclitaxel in patients with cancer: a meta-analysis.

Nab-paclitaxel, a Cremophor EL-free formulation of paclitaxel, is used to treat various malignancies. Peripheral neuropathy is one of its major toxicities, although the overall incidence remains unclear. We performed a meta-analysis to calculate the incidence of peripheral neuropathy in cancer patients treated with nab-paclitaxel and to compare the relative risk (RR) with conventional taxanes. The electronic databases were searched for relevant clinical trials. Eligible studies included phase II and III prospective clinical trials of cancer patients treated with nab-paclitaxel with toxicity profile on peripheral neuropathy. Statistical analyses were done to calculate summary incidences, RRs and 95% confidence intervals (CI), using fixed-effects or random-effects models based on the heterogeneity of the included studies. Nineteen trials were selected for the meta-analysis, yielding a total of 2878 cancer patients. The overall incidences of peripheral neuropathy (all-grade) was 51.0% (95% CI: 45.1-57.6%), and that of high-grade peripheral neuropathy was 12.4% (9.8-15.7%). The RRs of peripheral neuropathy of nab-paclitaxel compared to taxanes were not increased for all-grade and high-grade peripheral neuropathy. Nab-paclitaxel is associated with an increased risk of developing peripheral neuropathy. Future clinical studies are still needed to investigate the risk reduction and possible use of nab-paclitaxel.

Evaluation of two different doses of weekly nab-paclitaxel (NP) in older breast cancer (BC) patients (pts).

9531 Background: NP compares favorably with conventional taxanes in terms of safety, efficacy and convenience of administration. These features make NP an interesting agent for evaluation in elderl...

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer patients: prospective evaluation of activity, safety, and quality of life

BackgroundA prospective, multicenter trial was undertaken to assess the activity, safety, and quality of life of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer (MBC).Patients and methodsFifty-two women with HER2-negative MBC who were candidates for second-line chemotherapy for the metastatic disease were enrolled and treated at three centers in Northern Italy. All patients had previously received taxane-based chemotherapy in the adjuvant or first-line metastatic setting. Single-agent nab-paclitaxel was given at the dose of 260 mg/m2 as a 30-minute intravenous infusion on day 1 each treatment cycle, which lasted 3 weeks, in the outpatient setting. No steroid or antihistamine premedication was provided. Treatment was stopped for documented disease progression, unacceptable toxicity, or patient refusal.ResultsAll of the enrolled patients were evaluable for the study endpoints. The objective response rate was 48% (95% CI, 31.5%–61.3%) and included complete responses from 13.5%. Disease stabilization was obtained in 19 patients and lasted >6 months in 15 of them; the overall clinical benefit rate was 77%. The median time to response was 70 days (range 52–86 days). The median progression-free survival time was 8.9 months (95% CI, 8.0–11.6 months, range 5–21+ months). The median overall survival point has not yet been reached. Toxicities were expected and manageable with good patient compliance and preserved quality of life in patients given long-term treatment.ConclusionOur results showed that single-agent nab-paclitaxel 260 mg/m2 every 3 weeks is an effective and well tolerated regimen as second-line chemotherapy in HER2-negative, taxane-pretreated MBC patients, and that it produced interesting values of objective response rate and progression-free survival without the concern of significant toxicity. Specifically, the present study shows that such a regimen is a valid therapeutic option for that ‘difficult to treat’ patient population represented by women who at the time of disease relapse have already received the most active agents in the adjuvant and/or metastatic setting (ie, conventional taxanes).

Efficacy of Dose Dense Doxorubicin and Cyclophosphamide Followed by Paclitaxel versus Conventional Dose Doxorubicin, Cyclophosphamide Followed by Paclitaxel or Docetaxel in Patients with Node-Positive Breast Cancer

Adding taxanes to adjuvant antracycline and cyclophosphamide (AC) in combination may provide significant improvement in node-positive and high risk node-negative breast cancer (BC) patients. However, the optimal dose and the role of dose-dense (DD) chemotherapy have yet to be determined. The aim of this study was to compare the efficacy of a DD paclitaxel (P)-AC combination with conventional weekly P-AC or docetaxel D-AC combinations in patients with node-positive breast cancer. Newly diagnosed 280 node-positive BC patients diagnosed from 1998 to 2013 in three clinics were retrospectively analyzed. Demographic and medical data were collected from the medical charts. Patients were categorized to 3 groups according to treatment arms: arm A, ddAC-P; arm B, weekly P and AC combination; and arm C; T and AC combination. Adjuvant trastuzumab was added for HER2-positive patients. Kaplan-Meier survival analysis was carried out for disease free survival (DFS) and overall survival (OS). The log-rank test was used to examine the statistical significance of the differences observed between the groups. Two-sided P values <0.05 were considered statistically significant. Of the total of 280 patients, 101 were in arm A, 114 in arm B and 65 in arm C.The median ages were 49, 50 and 46, respectively (p=0.11). Median follow-up was 39 (3-193) months. Stage, lymphovascular and perineural invasion, receptor patern, and menopausal status were similar in the 3 treatment arms, but HER2 positivity was significantly lower in arm A, compared to arms B and C (25.7%, 53.1%, 41.5% in arms A, B and C, respectively; p<0.001). Also grade 3 tumors were significantly less frequent in treatment arm A compared to arm B and C (27.3%, 56.8% and 49.2% , respectively, p=0.01). Afterunivariate and multivariate analysis were performed, 3-year DFS rates were 89%, 81%, and 75%, respectively (p=0.12) and three year OS rates were 96.6%, 89%, and 75% (p=0.62). In this study, no significant difference was found between adjuvant dose dense and conventional taxane treatment regimens.

The Efficacy and Safety of Preoperative Chemotherapy With Triweekly Abraxane and Cyclophosphamide Followed by 5-Fluorouracil, Epirubicin, and Cyclophosphamide Therapy for Resectable Breast Cancer: A Multicenter Clinical Trial

BackgroundIt has been reported that tri-weekly Abraxane therapy has better outcomes in recurrent breast cancer than tri-weekly Cremophor-based taxol therapy, and that cyclophosphamide combined with taxane shows an enhanced antitumor effect. We conducted a phase II clinical trial of preoperative chemotherapy with a combination of TRI-ABC. Patients and MethodsFrom September 2011 to September 2013, 4 cycles of preoperative chemotherapy with TRI-ABC followed by 4 cycles of FEC were administered in patients with resectable breast cancer. In patients with HER2-positive breast cancer, tri-weekly Trastuzumab was administered with TRI-ABC. The primary end point was the pathological complete response (pCR) rate in the breasts and lymph nodes. ResultsThe treatment outcomes and safety were evaluated in 54 patients who received at least 1 dose of chemotherapy. All patients underwent radical surgery, and the overall pCR rate of 37% (20 of 54) was achieved. The pCR rates according to each subtype were 8% (2 of 24) in hormone receptor (HR)-positive HER2-negative breast cancer, 56% (5 of 9) in HR-positive HER2-positive breast cancer, 63% (5 of 8) in HR-negative HER2-positive breast cancer, and 62% (8 of 13) in triple-negative breast cancer. Multivariate analysis revealed that HR negativity and HER2 positivity were predictive factors of pCR. Clinical response was observed in 49 patients (91%). The safety profile was acceptable. ConclusionPreoperative chemotherapy with TRI-ABC followed by FEC showed high efficacy and excellent safety. Further clinical studies should be conducted to compare the efficacy of TRI-ABC followed by FEC with conventional taxane–anthracycline regimens.