PAM50 proliferation score as a predictor of weekly paclitaxel benefit in breast cancer.
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ABSTRACT:
SUBMITTER: Martin M
PROVIDER: S-EPMC3608881 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundWe compared the efficacy of two different taxanes, docetaxel and paclitaxel, given either weekly or every 3 weeks, in the adjuvant treatment of breast cancer.MethodsWe enrolled 4950 women with axillary lymph node-positive or high-risk, lymph node-negative breast cancer. After randomization, all patients first received 4 cycles of intravenous doxorubicin and cyclophosphamide at 3-week intervals and were then assigned to intravenous paclitaxel or docetaxel given at 3-week intervals for 4 cycles or at 1-week intervals for 12 cycles. The primary end point was disease-free survival.ResultsAs compared with patients receiving standard therapy (paclitaxel every 3 weeks), the odds ratio for disease-free survival was 1.27 among those receiving weekly paclitaxel (P=0.006), 1.23 among those receiving docetaxel every 3 weeks (P=0.02), and 1.09 among those receiving weekly docetaxel (P=0.29) (with an odds ratio >1 favoring the groups receiving experimental therapy). As compared with standard therapy, weekly paclitaxel was also associated with improved survival (odds ratio, 1.32; P=0.01). An exploratory analysis of a subgroup of patients whose tumors expressed no human epidermal growth factor receptor type 2 protein found similar improvements in disease-free and overall survival with weekly paclitaxel treatment, regardless of hormone-receptor expression. Grade 2, 3, or 4 neuropathy was more frequent with weekly paclitaxel than with paclitaxel every 3 weeks (27% vs. 20%).ConclusionsWeekly paclitaxel after standard adjuvant chemotherapy with doxorubicin and cyclophosphamide improves disease-free and overall survival in women with breast cancer. (ClinicalTrials.gov number, NCT00004125 [ClinicalTrials.gov].).
| S-EPMC2743943 | biostudies-literature
Project description:The PAM50 gene expression subtypes and the associated risk of recurrence (ROR) score are used to predict the risk of recurrence and the benefits of adjuvant therapy in early-stage breast cancer. The Prosigna assay includes the PAM50 subtypes along with their clinicopathological features, and is approved for treatment recommendations for adjuvant hormonal therapy and chemotherapy in hormone-receptor-positive early breast cancer. The Prosigna test utilizes RNA extracted from macrodissected tumor cells obtained from formalin-fixed, paraffin-embedded (FFPE) tissue sections. However, RNA extracted from fresh-frozen (FF) bulk tissue without macrodissection is widely used for research purposes, and yields high-quality RNA for downstream analyses. To investigate the impact of the sample preparation approach on ROR scores, we analyzed 94 breast carcinomas included in an observational study that had available gene expression data from macrodissected FFPE tissue and FF bulk tumor tissue, along with the clinically approved Prosigna scores for the node-negative, hormone-receptor-positive, HER2-negative cases (n = 54). ROR scores were calculated in R; the resulting two sets of scores from FFPE and FF samples were compared, and treatment recommendations were evaluated. Overall, ROR scores calculated based on the macrodissected FFPE tissue were consistent with the Prosigna scores. However, analyses from bulk tissue yielded a higher proportion of cases classified as normal-like; these were samples with relatively low tumor cellularity, leading to lower ROR scores. When comparing ROR scores (low, intermediate, and high), discordant cases between the two preparation approaches were revealed among the luminal tumors; the recommended treatment would have changed in a minority of cases.
| S-EPMC8657125 | biostudies-literature
Project description:BackgroundPaclitaxel treatment produces significant peripheral neuropathy, but the time course of neuropathy development and outcomes are unclear. Dose reduction is the only strategy to prevent neurotoxicity, however, the impact of dose-reduction on neuropathy outcomes remains unknown. This study aimed to prospectively evaluated neuropathy development from weekly paclitaxel treatment and evaluate the impact of dose-reduction on post-treatment neuropathy outcomes.Patients and methodsBreast cancer patients receiving paclitaxel (80mg/m2 ) weekly for 12-weeks were prospectively assessed using patient reported (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity; FACTGOG-Ntx), clinical (Total Neuropathy Score clinical version; TNSc) and neurophysiological measures up to 12-months post completion. The impact of dose-reduction on post-treatment (3.6 ± 0.1 months) clinical and patient reported outcomes was evaluated in 105 weekly paclitaxel-treated patients.ResultsSignificant neuropathy was present by 6-weeks across patient-reported, clinical, and objective neurophysiological assessments, increasing in prevalence and severity over the treatment course. Limited recovery occurred, with significant neuropathy being maintained up to 12 months (p < .05). Patients who received dose reduction had worse patient reported (FACT-GOG-Ntx: 40.2 ± .1.4) and clinical neuropathy outcomes (TNSc: 4.3 ± 0.4) compared to those who received the full dose (FACT-GOG-Ntx: 45.9 ± 0.9; TNSc: 3.3 ± 0.3, p < .05). Patients who ceased treatment early demonstrated the worse deficits (TNSc: 5.0 ± 0.6; FACT-GOG-Ntx: 37.3 ± 2.7) compared to those who received the complete dose (TNSc: 3.5 ± 0.3; FACT-GOG-Ntx: 45.3 ± 0.9, p < .05).ConclusionWeekly paclitaxel produces symptomatic and objective neuropathy early in the treatment course which can persist. Dose reduction does not necessarily lead to more favorable neuropathy outcomes, with individual risk factors likely important in addition to cumulative dose.Implications for practiceWeekly paclitaxel schedules are extensively used in breast cancer. Patients may develop symptomatic and objective neuropathy early in the treatment course, with these individuals requiring closer monitoring. Furthermore, neuropathy is a long-term sequela that may impact quality of life and require appropriate supportive services. Results suggest that dose reduction does not necessarily lead to better neuropathy outcomes. Understanding schedule-specific toxicity and risk factors for neuropathy will be critical to determining individualized treatment strategies and improving quality of life in breast cancer survivors.
| S-EPMC8100541 | biostudies-literature
Project description:Although nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is approved to be given every 3 weeks, weekly use of this drug is becoming a new standard of care in patients with metastatic breast cancer (MBC). This prospective Phase II study was conducted to improve the efficacy of weekly nab-paclitaxel with cisplatin in MBC patients. Seventy-three women with recurrent or MBC were eligible for participation. Nab-paclitaxel was administered weekly at a dose of 125 mg/m(2) on day 1, day 8, and day 15, followed by cisplatin 75 mg/m(2) on day 1, repeated every 28 days with a maximum of 6 cycles. The primary objective was investigator-assessed overall response rate (ORR). A high ORR of 67.1% was obtained, with rates of 80.6% for the first-line patients and 80% for patients not pretreated with taxanes. Among those who had objective responses, a large percentage of patients (83.7%) showed quickly remarkable tumor shrinkage during the first two cycles. The median progression-free and overall survival times were 9.8 and 26.9 months, respectively. For the patients receiving first-, second-, and third-line therapy or beyond, median progression-free survival was 11.7, 7.7, and 7.6 months, respectively (P=0.005). Molecular subtype was not significantly associated with ORR or disease progression. Grade 4 neutropenia occurred in 46 patients (63.0%), with febrile neutropenia found in 9 patients (12.3%). Grade 3 peripheral neuropathy was an accumulated dose-limiting toxicity occurring in 19 patients (26.0%). Efficacy of weekly nab-paclitaxel can be improved by adding cisplatin. The doublet is highly effective, with quick response, manageable toxicity, and possible equivalence across molecular subtypes in MBC patients.
| S-EPMC3964033 | biostudies-literature
Project description:Purpose: Hormone receptor-positive (HR+) breast cancer is clinically and biologically heterogeneous, and subgroups with different prognostic and treatment sensitivities need to be identified.Experimental Design: Research-based PAM50 subtyping and expression of additional genes was performed on 63 patients with HR+/HER2- disease randomly assigned to neoadjuvant multiagent chemotherapy versus endocrine therapy in a phase II trial. The biology associated with treatment response was used to derive a PAM50-based chemoendocrine score (CES). CES's predictive ability was evaluated in 4 independent neoadjuvant data sets (n = 675) and 4 adjuvant data sets (n = 1,505). The association of CES, intrinsic biology, and PAM50 risk of relapse (ROR) was explored across 6,007 tumors.Results: Most genes associated with endocrine sensitivity were also found associated with chemotherapy resistance. In the chemotherapy test/validation data sets, CES was independently associated with pathologic complete response (pCR), even after adjusting for intrinsic subtype. pCR rates of the CES endocrine-sensitive (CES-E), uncertain (CES-U), and chemotherapy-sensitive (CES-C) groups in both data sets combined were 25%, 11%, and 2%, respectively. In the endocrine test/validation data sets, CES was independently associated with response. Compared with ROR, >90% of ROR-low and ROR-high tumors were identified as CES-E and CES-C, respectively; however, each CES group represented >25% of ROR-intermediate disease. In terms of survival outcome, CES-C was associated with poor relapse-free survival in patients with ROR-intermediate disease treated with either adjuvant endocrine therapy only or no adjuvant systemic therapy, but not in patients treated with (neo)adjuvant chemotherapy.Conclusions: CES is a genomic signature capable of estimating chemoendocrine sensitivity in HR+ breast cancer beyond intrinsic subtype and risk of relapse. Clin Cancer Res; 23(12); 3035-44. ©2016 AACR.
| S-EPMC5449267 | biostudies-literature
Project description:Background. We performed a randomized phase II study comparing efficacy and toxicity of weekly paclitaxel 80?mg/m(2) (Weetax) with three weekly docetaxel 75?mg/m(2) (Threetax), both in combination with oral capecitabine 1000?mg/m(2) twice daily for 2 weeks followed by a 1-week break. Patients. Thirty-seven women with confirmed metastatic breast cancer were randomized. Results. Median TTF was 174 (Weetax) versus 147 days (Threetax) (P=0.472). Median OS was 933 (Weetax) versus 464 days (Threetax) (P=0.191). Reasons for TTF were PD 8/18 (Weetax), 9/19 (Threetax); and toxicity: 8/18 (Weetax), 8/19 (Threetax). ORR was 72% (Weetax) versus 26% (Threetax) (P = 0.01). The Threetax-combination resulted in a higher incidence of leuco-/neutropenia compared to Weetax. Grade II anemia was more pronounced in the Weetax group. No difference was found in quality of life. Conclusion. Taxanes in combination with capecitabine resulted in a high level of toxicity. Taxanes and capecitabine should be considered given sequentially and not in combination.
| S-EPMC3265117 | biostudies-literature
Project description:Paclitaxel is one of the most frequently used chemotherapeutic agents for the treatment of breast cancer patients. Using a candidate gene approach, we hypothesized that polymorphisms in genes relevant to the metabolism and transport of paclitaxel are associated with treatment efficacy and toxicity. Patient and tumor characteristics and treatment outcomes were collected prospectively for breast cancer patients treated with paclitaxel-containing regimens in the neoadjuvant setting. Treatment response was measured before and after each phase of treatment by clinical tumor measurement and categorized according to RECIST criteria, while toxicity data were collected from physician notes. The primary endpoint was achievement of clinical complete response (cCR) and secondary endpoints included clinical response rate (complete response+partial response) and grade 3+ peripheral neuropathy. The genotypes and haplotypes assessed were CYP1B1*3, CYP2C8*3, CYP3A4*1B/CYP3A5*3C, and ABCB1*2. A total of 111 patients were included in this study. Overall, cCR was 30.1% to the paclitaxel component. CYP2C8*3 carriers (23/111, 20.7%) had higher rates of cCR (55% vs. 23%; OR=3.92 [95% CI: 1.46-10.48], corrected p=0.046). In the secondary toxicity analysis, we observed a trend toward greater risk of severe neuropathy (22% vs. 8%; OR=3.13 [95% CI: 0.89-11.01], uncorrected p=0.075) in subjects carrying the CYP2C8*3 variant. Other polymorphisms interrogated were not significantly associated with response or toxicity. Patients carrying CYP2C8*3 are more likely to achieve clinical complete response from neoadjuvant paclitaxel treatment, but may also be at increased risk of experiencing severe peripheral neurotoxicity.
| S-EPMC3727245 | biostudies-literature
Project description:The therapeutic goals in metastatic breast cancer (MBC) remain palliative in nature, aimed at controlling symptoms, improving or maintaining quality of life and prolonging survival. The advent of new drugs and new formulations of standard agents has led to better outcomes in patients with advanced or metastatic disease. These developments have also allowed a tailored therapeutic approach, in which the molecular biology of the tumour, the treatment history, and patient attitudes are taken into account in the decision-making process. Targeting drug delivery to the tumour is a promising mean of increasing the therapeutic index of highly active agents such as the taxanes, and nanoparticle albumin-bound paclitaxel (nab-paclitaxel), the first nanotechnology-based drug developed in cancer treatment, is one such advance. Data from randomized trials support the efficacy of single-agent nab-paclitaxel as first-line and further treatment lines in MBC at the registered 3-weekly schedule of 260 mg/m(2), but emerging evidence suggests its activity as a weekly regimen or combined with other agents in various clinical scenarios. Thus, nab-paclitaxel seems to offer flexibility in terms of dosing schedules, allowing physicians to tailor the dose according to different clinical situations. This paper reviews the clinical trial background for nab-paclitaxel in MBC, focusing on specific 'difficult-to-treat' patient populations, such as taxane-pretreated or elderly women, as well as those with triple-negative, HER2-positive and poor-prognostic-factors disease. Moving beyond evidence-based information, 'real life' available experiences are also discussed with the aim of providing an update for daily clinical practice.
| S-EPMC4872255 | biostudies-literature
Project description:The goal of this Phase I/II trial is to assess the safety and efficacy of administering durvalumab concurrent with weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide (ddAC) neoadjuvant therapy for stages I-III triple-negative breast cancer. The primary endpoint is pathologic complete response (pCR:ypT0/is, ypN0). The response was correlated with PDL1 expression and stromal tumor-infiltrating lymphocytes (sTILs). Two dose levels of durvalumab (3 and 10 mg/kg) were assessed. PD-L1 was assessed using the SP263 antibody; ≥1% immune and tumor cell staining was considered positive; sTILs were calculated as the area occupied by mononuclear inflammatory cells over the total intratumoral stromal area. 59 patients were evaluable for toxicity and 55 for efficacy in the Phase II study (10 mg/kg dose). No dose-limiting toxicities were observed in Phase I. In Phase II, pCR rate was 44% (95% CI: 30-57%); 18 patients (31%) experienced grade 3/4 treatment-related adverse events (AE), most frequently neutropenia (n = 4) and anemia (n = 4). Immune-related grade 3/4 AEs included Guillain-Barre syndrome (n = 1), colitis (n = 2), and hyperglycemia (n = 2). Of the 50 evaluable patients for PD-L1, 31 (62%) were PD-L1 positive. pCR rates were 55% (95% CI: 0.38-0.71) and 32% (95% CI: 0.12-0.56) in the PD-L1 positive and negative groups (p = 0.15), respectively. sTIL counts were available on 52 patients and were significantly higher in the pCR group (p = 0.0167). Concomitant administration of durvalumab with sequential weekly nab-paclitaxel and ddAC neoadjuvant chemotherapy resulted in a pCR rate of 44%; pCR rates were higher in sTIL-high cancers.
| S-EPMC7870853 | biostudies-literature
Project description:PurposeWe tested the hypothesis that Akt-Ser473 phosphorylation (pAkt) predicts benefit from the sequential addition of paclitaxel to adjuvant doxorubicin plus cyclophosphamide (AC) chemotherapy in patients with node-positive breast cancer participating in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-28 trial.Patients and methodsPrimary tumors from the NSABP B-28 trial tissue microarray were available from 1,581 of 3,060 patients who were randomly assigned to receive either four cycles of AC alone or followed by four cycles of paclitaxel. Immunohistochemistry and quantitative analysis of pAkt were performed at the National Cancer Institute blinded to clinical outcome. Association between pAkt and clinical outcome was assessed using multivariate Cox modeling adjusting for age, tumor size, number of positive nodes, tumor grade, estrogen receptor status, and human epidermal growth factor receptor 2 status.ResultsWith a median follow-up of 9.1 years, there were no differences in disease-free survival (adjusted hazard ratio [HR], 1.02; P = .81) or overall survival (HR, 0.97; P = .80) with and without receiving paclitaxel among 975 patients with pAkt-negative tumors. In 606 patients with pAkt-positive tumors, the sequential addition of paclitaxel resulted in a 26% improvement in disease-free survival (HR, 0.74; P = .02) or a 20% improvement in overall survival (HR, 0.80; P = .17).ConclusionpAkt significantly predicts disease-free benefit from the sequential addition of paclitaxel to AC chemotherapy in patients with node-positive breast cancer. Patients with pAkt-negative breast tumors do not appear to benefit from the addition of paclitaxel.
| S-EPMC2903333 | biostudies-literature