Role of p53 mutations in clinical and pathological responses in an open-label study of capecitabine (C) and docetaxel (D) as neoadjuvant treatment for patients with recently diagnosed HER2-neu negative (HER2-) breast cancer (BC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 11022-11022
Author(s):  
S. Truong ◽  
N. Patten ◽  
D. Tripathy ◽  
S. Gluck ◽  
C. Moisa ◽  
...  
Keyword(s):  
Genomic Dna ◽  
Neoadjuvant Treatment ◽  
P53 Mutation ◽  
P53 Mutations ◽  
Site Mutation ◽  
Open Label ◽  
Exon 2 ◽  
Mutation Status ◽  
Single Base ◽  
Her2 Breast Cancer

11022 Background: The tumor suppressor gene p53 plays a key role in multiple cellular pathways controlling proliferation, survival, and genomic integrity. Disruption of its function promotes checkpoint defects, genomic instability and inappropriate survival leading to uncontrolled proliferation of damaged cells. The relationship of p53 mutation status to the outcome of patients suggests that p53 mutation status is a potential prognostic and predictive indicator of survival. Immunohistochemical analysis cannot accurately identify p53 mutation status and cannot differentiate between the several functional defects that arise from mutations at specific sites of this multifunctional gene. Methods: The primary objective is to define the rate of pCR in the affected breast after neoadjuvant C+D±T for HER2- or HER2+ BC pts, respectively. Eligibility: infiltrating HER2- or HER2+ stage II/III BC with no evidence of metastases and no prior systemic or local primary treatment. Four 3-week cycles consisted of C 825 mg/m2 bid on days 1–14 and D 75 mg/m2 on day 1. HER2+ pts also received T 4 mg/kg x1 on day -1 followed by 2 mg/kg weekly. Enrollment of 99 HER2- patients is planned. The AmpliChip p53 test (Roche Diagnostics, in development), a DNA microarray-based sequencing method, was used to analyze the p53 mutation status. The AmpliChip p53 test is designed to detect all substitution single base changes and single base deletion in all coding regions of the p53 gene. The genomic DNA was extracted from a biopsy sample from each patient and 50–100 ng genomic DNA was used. Results: A total of 47 p53 mutations were found in 44 of 88 (50%) patients, including 32 missense, 6 frameshift, 8 non-sense, and 1 splice site mutation, and were widely distributed in exon 2, 4, 5, 6, 7, 8, 9 and 10. The p53 mutation status including the type and location will be analyzed in relation to clinical and pathological response. Updated data will be presented. Conclusions: The AmpliChip p53 test is a rapid, accurate, and standardized way to detect p53 mutations. These findings suggest that p53 mutations occur in at least 50% of recently diagnosed BC. No significant financial relationships to disclose.

An open-label randomized, multicenter, phase II study on neoadjuvant treatment  with trastuzumab plus docetaxel versus trastuzumab plus docetaxel plus bevacizumab according to positron emission tomography (PET) value modification in patients with early stage HER2-positive breast cancer (AVATAXHER): Design description.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS646-TPS646 ◽  
Author(s):  
Alexandre Cochet ◽  
Khaldoun Kerrou ◽  
Jean-Marc A. Nabholtz ◽  
Florent Cachin ◽  
Jean-Yves Pierga ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Phase Ii ◽  
Fdg Pet ◽  
Neoadjuvant Treatment ◽  
High Rate ◽  
Emission Tomography ◽  
Open Label ◽  
Post Surgery ◽  
Her2 Breast Cancer

TPS646 Background: For patients with early HER2+ breast cancer at diagnosis, addition of trastuzumab (T) to 6 cycles of preoperative docetaxel (D) can reach a pathological complete response (pCR) in ~50% of cases, and a high rate of conservative surgery. pCR can be predicted by changes of Fluorodeoxyglucose (FDG) tumor uptake evaluated by Positon Emission Tomography (PET) after one cycle of therapy. In order to increase this pCR rate, adding an antiangiogenic compound could be considered. Pre-clinical and phase I-II data support that the combination of bevacizumab (B) and T is synergistic and safe when patients are chemotherapy naïve. The neoadjuvant AVATAXHER trial (EUDRACT 2009-013410-26) investigates the potential increase of pCR rate by combining B with T and D for patients with HER2+ breast cancer who are not predicted for pCR by FDG PET. Methods: In this multicenter, open-label, phase II trial, 2 phases are planned after a selection period: phase I: all patients receive two cycles of therapy combining T (8 mg/kg at the first cycle, then 6 mg/kg) and D (100 mg/m2). FDG PET is also performed within 7 days before cycle 1 (baseline) and less than 3 days before cycle 2 in order to calculate changes of the tumor FDG uptake between baseline and after cycle 1 (ΔSUV). Phase 2: if ΔSUV≥70%, patients will continue to receive T and D for (cycles 3 to 6: D 100 mg/m2 + T 6 mg/kg); if ΔSUV<70%, patients are randomized 2:1 to arm A (cycles 3 to 6 D 100 mg/m2 + T 6 mg/kg + B 15 mg/kg) or arm B ( cycles 3 to 6: D 100 mg/m2 + T 6 mg/kg). The primary endpoint is pCR rate evaluated post-surgery 4 to 6 weeks after the last treatment of cycle 6. Enrolment began in May 2010 and 125 patients were to be recruited in 26 sites. According to the hypothesis that 60% of patients will have a ΔSUV<70%, it is presumed that 72 patients will be randomized. There are currently 107 patients included (as of 06 January 2012 ), 95 of them reached the phase 1; 52 of them (55%) showed a ΔSUV<70% and after randomization 34 were included in arm A and 18 in arm B.

The Combination of p53 Mutation and neu/erbB-2 Amplification Is Associated With Poor Survival in Node-Negative Breast Cancer

2004 ◽  
Vol 22 (1) ◽  
pp. 86-96 ◽  
Author(s):  
Shelley B. Bull ◽  
Hilmi Ozcelik ◽  
Dushanthi Pinnaduwage ◽  
Martin E. Blackstein ◽  
Donald A.J. Sutherland ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prognostic Factors ◽  
Relative Risk ◽  
Disease Recurrence ◽  
P53 Mutation ◽  
Consecutive Series ◽  
P53 Mutations ◽  
Mutation Status ◽  
Node Negative ◽  
Single Stranded Conformational Polymorphism

Purpose Increases in neu/erbB-2 have been implicated in breast cancer prognosis, but do not predict all recurrences. On the basis of evidence that p53 mutation is involved in the development of human neoplasia, we examined the prognostic value of p53 alterations in combination with neu/erbB-2 amplification. Patients and Methods A consecutive series of women were observed for recurrence and death (median follow-up of 85 months) and tumors from 543 individuals were analyzed for p53 mutation status and neu/erbB-2 amplification. Exons 4 through 10 of the p53 gene were analyzed by single-stranded conformational polymorphism and mutations were confirmed by DNA sequencing. The association of p53 mutation status and neu/erbB-2 amplification with risk of recurrence and death was examined in survival analyses with traditional and histologic markers as prognostic factors. Results p53 mutations occurred in 24.5% of the axillary node-negative breast carcinomas. Mutations were more frequent in carcinomas with neu/erbB-2 amplification: 38.9% compared with only 20.9% in those without neu/erbB-2 amplification. We found elevated risks of disease recurrence and overall mortality in patients with both p53 mutation and neu/erbB-2 amplification in their tumor compared with patients with neither or only one of the alterations. This increase persisted with adjustment for other prognostic factors (relative risk, 2.32; P = .002 for recurrence; relative risk, 2.22; P = .004 for death). Conclusion Evaluation of tumors for p53 mutations may be beneficial to identify women at higher risk of disease recurrence and death when the tumor has neu/erbB-2 amplification, but in the absence of neu/erbB-2 amplification, the presence of p53 mutation may not provide additional independent prognostic information.

scholarly journals Modulation of the Ribonucleotide Reductase-Antimetabolite Drug Interaction in Cancer Cell Lines

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Jun Zhou ◽  
Paula Oliveira ◽  
Xueli Li ◽  
Zhengming Chen ◽  
Gerold Bepler
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Drug Efficacy ◽  
Cancer Cell Lines ◽  
P53 Mutation ◽  
Cytotoxic Agents ◽  
P53 Mutations ◽  
Mutation Status ◽  
Apparent Relationship ◽  
The Impact

RRM1 is a determinant of gemcitabine efficacy in cancer patients. However, the precision of predicting tumor response based on RRM1 levels is not optimal. We used gene-specific overexpression and RNA interference to assess RRM1's impact on different classes of cytotoxic agents, on drug-drug interactions, and the modulating impact of other molecular and cellular parameters. RRM1 was the dominant determinant of gemcitabine efficacy in various cancer cell lines. RRM1 also impacted the efficacy of other antimetabolite agents. It did not disrupt the interaction of two cytotoxic agents when combined. Cell lines with truncation, deletion, and null status of p53 were resistant to gemcitabine without apparent relationship to RRM1 levels. Pemetrexed and carboplatin sensitivity did not appear to be related to p53 mutation status. The impact of p53 mutations in patients treated with gemcitabine should be studied in prospective clinical trials to develop a model with improved precision of predicting drug efficacy.

Correlations between P53 Mutation Status and Texture Features of CT Images for Hepatocellular Carcinoma

2019 ◽  
Vol 58 (01) ◽  
pp. 042-049
Author(s):  
Hongzhen Wu ◽  
Xin Chen ◽  
Jiawei Chen ◽  
Yuqi Luo ◽  
Xinqing Jiang ◽  
...  
Keyword(s):  
Texture Features ◽  
Ct Images ◽  
P53 Mutation ◽  
P53 Mutations ◽  
Characteristic Analysis ◽  
Mutation Status ◽  
Mean Values ◽  
The Mean ◽  
Ct Data ◽  
Occurrence Matrix

Objectives To investigate the performance of texture analysis in characterizing P53 mutations of hepatocellular carcinomas (HCCs) based on computed tomography (CT). Methods A total of 63 HCC patients underwent CT scans and were tested for P53 mutations. Patients were divided into two groups of P53(−) and P53(+) according to the P53 scores. First- and second-order texture features were computed from the CT images and compared between groups using independent Student's t-test. A Spearman's correlation coefficient was used for correlations to assess the relationship between the different P53 sores and CT data. The performance of texture features in differentiating the P53 mutations of HCC was assessed using receiver operating characteristic analysis. Results The mean values of angular second moment (ASM; mean = 0.001) and contrast (mean = 194.727) for P53(−) were higher than those of P53(+). Meanwhile the mean values of correlation (mean = 0.735), sum variance (mean = 1,111.052), inverse difference moment (IDM; mean = 0.090), and entropy (mean = 3.016) for P53(−) were lower than those of P53(+). Significant correlations were found between P53 scores and ASM (r =  − 0.439), contrast (r =  − 0.263), correlation (r = 0.551), sum of squares (r = 0.282), sum variance (r = 0.417), IDM (r = 0.308), and entropy (r = 0.569). Five texture parameters (ASM, contrast, correlation, IDM, and entropy) were predictive of P53 mutation status, with areas under the curve ranging from 0.621 to 0.792. Conclusions There was a direct relationship between P53 mutations and gray-level co-occurrence matrix, but not with histograms for HCC patients. Correlation and entropy seemed to be the most promising in differentiating P53 (−) from P53(+).

Characterization of p53 Abnormalities in CLL Patients in Relation to IGVH Mutation Status and Previous Treatment.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2947-2947
Author(s):  
M. Trbusek ◽  
V. Kuhrova ◽  
J. Malcikova ◽  
J. Smardova ◽  
H. Francova ◽  
...  
Keyword(s):  
Hot Spots ◽  
Direct Sequencing ◽  
P53 Protein ◽  
Alkylating Agents ◽  
Previous Treatment ◽  
P53 Gene ◽  
P53 Mutation ◽  
P53 Mutations ◽  
Mutation Status ◽  
P53 Inactivation

Abstract Background: Although the defects in the p53 gene predispose CLL patients for inferior outcome, little is known about the reasons leading to inactivation of this tumor-suppressor. The p53 abnormalities were reported to be associated with unmutated IgVH subtype and may thus arise as a consequence of its more aggressive behaviour, but some reports point also to potentially damaging chemotherapy including alkylating agents. Aims: The aims of the study were to determine the spectrum of p53 mutations in CLL patients treated or monitored at our center and to correlate the data to mutation status of IgVH and to the previous treatment. Methods: We analyzed the status of the p53 gene in 144 patients diagnosed with CLL of all stages using functional analysis in yeasts (FASAY) supplemented by Western-blotting detection of p53 protein expression and I-FISH detection of p53 deletions. We used PCR and direct sequencing to analyze the IgVH rearrangements and mutation status. Results: Our comprehensive approach for monitoring of p53 abnormalities provided us the overall frequency of inactivation within the expected range (14%; usually reported between 10–15%). We noticed a very good overlap between the mutation of one and deletion of the second allele (93%) and between the mutation and corresponding p53 protein over-expression (92%). All the identified mutations in the p53 gene were unambigously determined by direct sequencing from yeast colonies harboring mutated phenotype. We did not find any p53 mutation (n=15) more than once and thus we do not see in our population neither the hot-spots published for CLL in p53 mutation database IARC (codons 248 and 273) nor the hot-spots reported in literature (codons 209 and 143). Inactivation of p53 ocurred markedly more frequently in subtype with unmutated IgVH compared to mutated one (16.7% vs. 5.3%). Moreover, two of the three IgVH mutated cases harbored just p53 deletion without accompanying mutation, slightly over background level. We noticed a very low frequency of the immunoglobulin gene VH3-21 (4.3% in our study vs. 11.2% reported by Tobin et al., Blood2002; 99: 2262–2264), which was recently reported to be mostly mutated and to be associated with p53 inactivation. Four of the six our cases manifested unmutated IgVH, with two of them showing deletions of p53 or ATM (p53-regulatory kinase), respectively. The overall treatment, which included alkylating agents in 43/48 cases, was markedly more frequent within the subgroup with germ-line IgVH (in 49% of patients) compared to group harboring mutated IgVH (in 7% of patients - none of them with p53 inactivation). In the former subgroup the p53 inactivation in the untreated and treated patients was very similar (17% vs. 20%). Conclusions: The spectrum of p53 mutations in our population is different from those reported in other studies. The inactivation of the p53 was in our study associated with unmutated IgVH locus and does not seem to be primarily the consequence of previous chemotherapy including alkylating agents. Supported by grants NR8445-3/2005, NR8443-3/2005 and NR8448-3/2005 provided by IGA of Ministry of Health of the Czech Republic.

Polycomb Complex Group Gene Mutations and Their Prognostic Relevance In 5-Azacitidine Treated Myelodysplastic Syndrome Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 125-125 ◽  
Author(s):  
Austin G Kulasekararaj ◽  
Azim M Mohamedali ◽  
Alexander E Smith ◽  
Nicholas C Lea ◽  
Aytug Kizilors ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Response Rate ◽  
Gene Mutations ◽  
P53 Mutation ◽  
Chromosome 7 ◽  
P53 Mutations ◽  
Mutation Status ◽  
Normal Cytogenetics ◽  
Polycomb Complex ◽  
Good Risk

Abstract Abstract 125 Polycomb gene complex mutations have been implicated in the pathogenesis of myeloid neoplasms. ASXL1, a epigenetic regulator of transcription by recruiting polycomb and trithorax complexes to the chromatin domain and EZH2 (histone methyltransferase) is the catalytic domain of polycomb repressive complex (PRC) 2, causing gene silencing by trimethylation of lysine 27 of histone 3(H3K27). To identify the role of mutations in ASXL1, EZH2 and their interaction with other mutations (P53, ras, c-cbl, IDH 1/2, BRAF), we analysed 63 MDS patients treated with 5-Azacitidine (Aza) at our institution. Mutation analysis was done by deep (454 FLX) and Sanger sequencing. SNP-6 karyotyping was also performed to correlate with mutation status. In 43 patients, samples were also analysed at various time points post aza treatment. The median age was 67 years (range 36–86 years), median number of courses 7(range 2–109), 90% (57/63) of patients belonged to high risk IPSS category. WHO category subtypes were; RA/RARS-1; RCMD-7; RAEB-37; s-AML (evolved from pre-existing MDS) -9, therapy related myeloid neoplasm (t-MDS/t-AML) -7 and CMML-2.IPSS cytogenetic subgroups were, good risk: 19, intermediate: 6, and poor risk: 38. Thirty six patients had chromosome 7 abnormalities either isolated (12/36) or with additional aberrations. The median time from diagnosis to treatment with aza was 7 months (range 1–42). The overall response rate to Aza was 48% (30/63) with a better survival in responders compared with non-responders (17.3 vs 10.2 months p<0.001). ASXL1 exon 12 mutations were present in 22/63 patients (35%), good risk cytogenetics (8/19), intermediate risk (4/6), isolated monosomy 7 patients (7/12) but none in the complex cytogenetics subgroup (p<0.02). EZH2 mutations were present in 4 of 18 patients with normal cytogenetics and 4/12 patients with isolated chromosome 7 abnormality. Five patients had both EZH2 and ASXL1 mutations. PRC mutant cases (25/63) had a better overall survival (OS) and progression free survival (PFS) compared with wild type cases (38/63) (OS;20.8 vs 11.9, p<0.007 and PFS 17.7 vs 8.5, p<0.004). Seven of 8 patients with EZH2 mutations responded to Aza (p<0.01) with 3 patients achieving CCyR, 2 CR and 2 marrow CR. There was no correlation with response to treatment and presence of ASXL1 mutations. The c1934dupG p. G646WfsX12 the frequent mutation (7/23, 30%) was not found in constitutional DNA P53 mutations were detected and quantified by high throughput sequencing in poor risk IPSS cytogenetic group (14/38) and were absent in patients with normal cytogenetics and isolated chromosome 7 abnormalities. EZH2 mutations were not detected in patients with P53 mutations and only 2/22 patients with ASXL1 had a concurrent P53 mutation, suggesting a possible mutual exclusivity of polycomb gene mutations and P53. All 14 patients with P53 mutation died (p<0.007) and 43% of patients with P53 mutations showed response to Aza. Sequential samples were available in 7 patients and changes in clone sizes were correlative of treatment response, with 3 patients achieving cytogenetic response with concurrent reduction in clone size. Two different mutations (double clones) of P53 was found in 6/14 mutant patients. The P53 mutation status correlated strongly with finding aberration of chromosome 17p by SNP array and positive P53 antibody staining on bone marrow trephine. The P53 mutant patients had a worse OS (8.9 vs 17.7 months, p<0.0001) and PFS (8.1 vs 12.7 months, p<0.006). IDH1and IDH2, C-Cbl, NRAS mutations occurred in 6/63 (10%), 4/63 (6%), 6/63 (10%) of patients respectively and did not correlate with clinical outcome. Age, IPSS cytogenetic risk group, WHO subtypes, overall response rate (ORR),progression to AML, P53 mutation status and presence of EZH2 and/or ASXLI mutation were used as co-variables in multivariate analysis.P53 mutation status (HR=5.3(2.3-11.8), p<0.0001) ORR (HR=0.27 (0.13-0.57), p<0.001) were established as independent prognostic variables influencing OS. This study shows that polycomb complex gene mutations are frequent particularly in relatively good cytogenetic subgroups of MDS. The presence of these mutations correlates with a significantly better OS and PFS following Aza therapy. P53 mutations are uncommon in patients that harbour polycomb complex gene mutations and the presence of P53 mutations do not correlate with response rate, however they remain a strong indicator of OS and PFS. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Phase II study of metronomic treatment with daily oral vinorelbine as first-line chemotherapy in patients with advanced/metastatic HR+/HER2− breast cancer resistant to endocrine therapy: VinoMetro—AGO-B-046

2021 ◽  
Author(s):  
Slavomir Krajnak ◽  
Thomas Decker ◽  
Lukas Schollenberger ◽  
Christian Rosé ◽  
Christian Ruckes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
First Line ◽  
Open Label ◽  
Oral Vinorelbine ◽  
Her2 Breast Cancer ◽  
Line Chemotherapy

Abstract Purpose Metronomic chemotherapy (MCT) is an increasingly used treatment option in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced/metastatic breast cancer (MBC) after failure of endocrine-based therapies. Methods VinoMetro was a multicentre, open-label, single-arm, phase II study of metronomic oral vinorelbine (VRL; 30 mg/day) as a first-line chemotherapy (CT) in patients with HR+/HER2− MBC after endocrine failure. The primary endpoint was the clinical benefit rate (CBR) at 24 weeks. Results Between January 2017 and April 2019, nine patients were enrolled. The CBR was 22.2% (90% confidence interval [CI] 4.1–55.0), p = 0.211. The median progression-free survival (PFS) was 12.0 weeks (95% CI 11.3–12.7). Grade 3–4 adverse events (AEs) occurred in 22.2% of patients. One patient died of febrile neutropenia. Conclusion VinoMetro (AGO-B-046) was closed early after nine patients and occurrence of one grade 5 toxicity in agreement with the lead institutional review board (IRB). Metronomic dosing of oral VRL in HR+/HER2− MBC as first-line CT after failure of endocrine therapies showed only limited benefit in this population. Trial registration number and date of registration ClinicalTrials.gov Identifier: NCT03007992; December 15, 2016.

New possibilities of neoadjuvant treatment of ER+ HER2- breast cancer in premenopausal patients

Pharmateca ◽  
2021 ◽  
Vol 7_2021 ◽  
pp. 56-60
Author(s):  
R.V. Orlova Orlova ◽  
A.A. Vakhitova Vakhitova ◽  
M.I. Gluzman Gluzman ◽  
◽  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Treatment ◽  
Her2 Breast Cancer ◽  
Premenopausal Patients
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