Lessons Learned
Results suggest that the combination of bevacizumab plus temozolomide is active in terms of response rate, survival, performance, quality of life, and cognition in elderly patients ...with glioblastoma multiforme with poor performance status.
Whether this combination is superior to temozolomide alone remains to be demonstrated by a randomized study.
Background
The optimal treatment of glioblastoma multiforme (GBM) in patients aged ≥70 years with a Karnofsky performance status (KPS) <70 is not established. This clinical trial evaluated the efficacy and safety of upfront temozolomide (TMZ) and bevacizumab (Bev) in patients aged ≥70 years and a KPS <70.
Materials and Methods
Patients aged ≥70 years with a KPS <70 and biopsy‐proven GBM were eligible for this multicenter, prospective, nonrandomized, phase II trial of older patients with impaired performance status. Treatment consisted of TMZ administered at 130–150 mg/m2 per day for 5 days every 4 weeks plus Bev administered at 10 mg/kg every 2 weeks.
Results
The trial included 66 patients (median age of 76 years; median KPS of 60). The median overall survival (OS) was 23.9 weeks (95% confidence interval CI, 19–27.6), and the median progression‐free survival (PFS) was 15.3 weeks (95% CI, 12.9–19.3). Twenty‐two (33%) patients became transiently capable of self‐care (i.e., KPS >70). Cognition and quality of life significantly improved over time during treatment. Grade ≥3 hematological adverse events occurred in 13 (20%) patients, high blood pressure in 16 (24%), venous thromboembolism in 3 (4.5%), cerebral hemorrhage in 2 (3%), and intestinal perforation in 2 (3%).
Conclusion
This study suggests that TMZ + Bev treatment is active in elderly patients with GBM with low KPS and has an acceptable tolerance level.
经验总结
结果表明, 对于患多形性恶性胶质瘤且体能状态欠佳的老年患者, 贝伐单抗+替莫唑胺联合治疗在缓解率、生存期、体能、生活质量和认知方面有效。
此联合治疗是否优于替莫唑胺单药治疗有待通过随机研究证明。
摘要
背景.尚未确定Karnofsky体能状态评分（KPS）<70、年龄≥70岁的多形性恶性胶质瘤（GBM）患者的最佳治疗。本临床试验评价了替莫唑胺（TMZ）和贝伐单抗（Bev）初期治疗在年龄≥70岁、KPS<70的患者中的疗效和安全性。
材料和方法.年龄≥70岁、KPS<70且患有经活检证实GBM的患者有资格参加本项针对体能状态受损年长患者的多中心、前瞻性、非随机、II期试验。治疗包括每4周一次、为期5天的TMZ 130–150mg/m2/天给药+每2周一次Bev 10mg/kg给药。
结果.该试验包括66例患者（中位年龄为76岁, 中位KPS为60）。中位总生存期（OS）为23.9周95%置信区间（CI）：19–27.6, 中位无进展生存期（PFS）为15.3周（95% CI：12.9–19.3）。22例（33%）患者暂时能够自我护理（即KPS>70）。治疗期间认知和生活质量得到显著改善。13例（20%）患者发生≥3级血液学不良事件, 16例（24%）患者发生高血压, 3例（4.5%）患者发生静脉血栓栓塞, 2例（3%）患者发生脑出血, 2例（3%）患者发生肠穿孔。
结论.本研究表明TMZ+Bev治疗在KPS较低的GBM老年患者中有效, 且耐受程度可接受。
Chemo‐induced thrombocytopenia is a limiting toxicity among patients receiving temozolomide (TMZ) as first‐line treatment for glioblastoma. We aimed to compare early platelet concentration kinetics, ...hematological safety profile, and impact on survival following the initiation of either the brand‐name or a generic TMZ formulation. A retrospective trial was conducted in patients suffering from newly diagnosed glioblastoma. Patients were treated with TMZ at 75 mg/m2 per day during six weeks, concomitantly with radiotherapy. Platelet concentration was collected each week. Primary endpoint was to perform a linear mixed‐effect model of platelet concentration kinetic over weeks. A total of 147 patients were included as follows: 96 received the brand‐name TMZ, and 51 received a generic TMZ formulation. Exposition to the generic was a significant variable that negatively influenced the platelet kinetics in the radiotherapy and concomitant TMZ phase, P = 0.02. Grade ≥3 chemo‐induced thrombocytopenia was more frequent in the generic group: 19.6% 95% CI 8.7‐30.5% vs 3.1% 0‐6.6%, P = 0.001. Exposition to the generic formulation of TMZ led to increase early treatment discontinuation due to TMZ‐induced thrombocytopenia and was a worsening independent prognostic factor on overall survival: adjusted HR 1.83 1.21‐2.8, P = 0.031. These data suggest that exposition to a generic formulation of TMZ vs the brand‐name product is associated with higher early platelet decrease leading to clinically relevant impacts on treatment schedule in glioblastoma. Further prospective trials are needed to confirm these results.
Purpose
Temozolomide (TMZ) is known to induce thrombocytopenia but no early predictive test has yet been clearly established. The aim of the study was to retrospectively identify and validate a ...threshold of early platelet variation predicting TMZ-induced thrombocytopenia during the TMZ phase in patients treated according to the Stupp protocol for glioblastoma.
Methods
A training set was used to analyze variations in platelet count occurring from the first week (W1) to week 6 (W6) during radiotherapy. Our aim was to identify the most relevant platelet decrease associated with TMZ-induced thrombocytopenia ≤ 100 G/L at day 28 during the TMZ phase. The performance of the threshold was confirmed in an independent validation set.
Results
Overall, 147 patients were included, 85 and 62 in the training and validation sets, respectively. Twenty-seven patients (18%) experienced at least one TMZ-induced thrombocytopenia in the TMZ phase. A platelet decrease at W6 ≥ 35% (∆W6 ≥ 35%) was identified as the best predictive variation with an AUC of 0.83, a sensitivity of 65%, and a specificity of 96%. In the validation set, ∆W6 ≥ 35% platelet variation was identified as an independent marker of TMZ-induced thrombocytopenia during the TMZ phase (OR 15.23 (95% CI 3.5–107.5)) corresponding to sensitivity of 77% (66–87%), specificity of 73% (62–84%), a positive predictive value of 42% (29–54%), and a negative predictive value of 92% (86–99%).
Conclusion
Platelet decrease at W6 ≥ 35% during the RT-TMZ phase is an early and simple predictive marker of clinically relevant TMZ-induced thrombocytopenia during TMZ maintenance.
One of the main challenges in cancer genetics is responding to the exponential demand for genetic counseling, especially in patients with breast and/or ovarian cancer. To address this demand, we have ...set up a new procedure, based on pre-genetic counseling telephone interviews (PTI) followed by routing of patients: D1, a PTI is scheduled within 14 days; D7–D14, genetic counselors perform a 20 min PTI in order to establish a pre-genetic counseling file, by collecting personal and family medical history
via
a structured questionnaire and; D10–17, routing: pre-genetic counseling appointment files are analyzed by a cancer geneticist with 3 possible conclusions: (a) priority face-to-face genetic counseling (FTFGC) appointment with a cancer geneticist, if the genetic test results have an immediate therapeutic impact; (b) non-priority FTFGC with a genetic counselor, or (c) no FTFGC required or substitution by a more appropriate index case. In the context of breast and/or ovarian cancer, 1012 patients received PTIs, 39.1% of which did not lead to FTFGC. The mean delay for non-priority FTFGC was maintained at 18 weeks and priority FTFGC appointments were guaranteed within 8 weeks. The required resources for 1012 patients was estimated at 0.12 FTE secretaries, 0.62 FTE genetic counselors and 0.08 FTE cancer geneticists and the procedure was shown to be cost-effective. This new procedure allows the suppression of up to 1/3 of appointments, guarantees priority for appointments with therapeutic impact and optimizes the interaction and breakdown of tasks between genetic counselors and cancer geneticists.
Genome-wide association studies (GWAS) have to date identified 94 genetic variants (single nucleotide polymorphisms (SNPs)) associated with risk of developing breast cancer. A score based on the ...combined effect of the 94 risk alleles can be calculated to measure the global risk of breast cancer. We aimed to test the hypothesis that the 94-SNP-based risk score is associated with clinico-pathological characteristics, breast cancer subtypes and outcomes in early breast cancer.
A 94-SNP risk score was calculated in 8703 patients in the PHARE and SIGNAL prospective case cohorts. This score is the total number of inherited risk alleles based on 94 selected SNPs. Clinical data and outcomes were prospectively registered. Genotyping was obtained from a GWAS.
The median 94-SNP risk score in 8703 patients with early breast cancer was 77.5 (range: 58.1-97.6). The risk score was not associated with usual prognostic and predictive factors (age; tumor, node, metastasis (TNM) status; Scarff-Bloom-Richardson grade; inflammatory features; estrogen receptor status; progesterone receptor status; human epidermal growth factor receptor 2 (HER2) status) and did not correlate with breast cancer subtypes. The 94-SNP risk score did not predict outcomes represented by overall survival or disease-free survival.
In a prospective case cohort of 8703 patients, a risk score based on 94 SNPs was not associated with breast cancer characteristics, cancer subtypes, or patients' outcomes. If we hypothesize that prognosis and subtypes of breast cancer are determined by constitutional genetic factors, our results suggest that a score based on breast cancer risk-associated SNPs is not associated with prognosis.
PHARE cohort: NCT00381901 , Sept. 26, 2006 - SIGNAL cohort: INCa RECF1098, Jan. 28, 2009.
Acquired estrogen receptor gene (
ESR1
) mutations have been recently reported as a marker of resistance to aromatase inhibitors in hormone receptor positive metastatic breast cancer. We ...retrospectively considered seven patients treated for metastatic breast cancer with available samples from the primary tumor before any treatment, cryopreserved metastasis removed during progression and concomitant plasmas. All these seven patients were in disease progression after previous exposure to aromatase inhibitors for at least 6 months, and were assessed for
ESR1
mutations detection in tumor and circulating DNA. For these patients, Sanger sequencing identified four metastases with clear
ESR1
mutation and one possible, whereas digital PCR identified six mutated metastases. Then, under blind conditions and using digital PCR, corresponding circulating
ESR1
mutations were successfully detected in four of these six metastatic breast cancer patients. Moreover, in two patients with serial blood samples following treatments exposure, the monitoring of circulating
ESR1
mutations clearly predicted disease evolution. In the context of high interest for
ESR1
mutations, our results highlight that these acquired recurrent mutations may be tracked in circulating tumor DNA and may be of clinical relevance for metastatic breast cancer patient monitoring.
What's new?
Acquired mutations in the estrogen‐receptor gene ESR1 can be a marker of resistance to aromatase inhibitors in metastatic breast cancer. In this study, the authors found that these mutations can be detected by digital PCR in circulating tumor DNA (ctDNA), and may predict the evolution of the disease. Because these mutations are recurrent, only a few assays are needed to define ESR1 mutational status. This method may thus prove useful in daily practice for the management of metastatic breast cancer patients.
Germline allele specific expression (ASE), resulting in a lowered expression of one of the
BRCA1
alleles, has been described as a possible predisposition marker in Hereditary Breast or Ovarian Cancer ...(HBOC), usable for molecular diagnosis in HBOC. The main objective of this prospective case–control study was to compare the proportion of ASE between controls without familial history of breast or ovarian cancer, and HBOC cases without
BRCA1
or
BRCA2
deleterious mutation.
BRCA1
ASE evaluated on three SNPs among controls and HBOC patients without deleterious mutation were assessed by pyrosequencing. The allelic ratios and the proportion of ASE were compared between controls and cases using a Student’s t test and a Fisher exact test, respectively. The linearity and reproducibility of the ASE dosage was demonstrated with R
2
> 0.99 and a coefficient of variation below 10 %, and ASE was detected in two positive controls harbouring
BRCA1
truncated mutations. In the heterozygote population, composed of 99/264 controls (37.5 %) and 96/227 patients (42.3 %), we detected a 5 % ASE without truncated mutations, in each population. We failed to detect any significant difference of ASE between controls and patients. So far,
BRCA1
Allelic specific expression is not usable in routine diagnosis as a possible predisposition marker in HBOC patients except for the detection of truncated mutations.
Glioblastoma is the most common malignant brain tumor in adults. Baseline health‐related quality of life (HRQoL) is a major subject of concern for these patients. We aimed to assess the independent ...prognostic value of HRQoL in unresectable glioblastoma (UGB) patients for death risk stratification. One hundred and thirty‐four patients with UGB were enrolled from the TEMAVIR trial. HRQoL was evaluated at baseline using the EORTC QLQ‐C30 and BN20 brain cancer module. Clinical and HRQoL parameters were evaluated in univariable and multivariable Cox analysis as prognostic factors for overall survival (OS). Performance assessment and internal validation of the final model were evaluated with Harrel's C‐index, calibration plot, and bootstrap sample procedure. Two OS independent predictors were identified: future uncertainty and sensitivity deficit. The final model exhibited good calibration and acceptable discrimination (C statistic = 0.63). The internal validity of the model was verified with robust uncertainties around the hazard ratio. The prognostic score identified three groups of patients with distinctly different risk profiles with median OS estimated at 16.2, 9.2, and 4.5 months. We demonstrated the additional prognostic value of HRQoL in UGB for death risk stratification and provided a score that may help to guide clinical management and stratification in future clinical trials.
We aimed to assess the independent prognostic value of HRQoL in unresectable glioblastoma (UGB) patients for death risk stratification. The prognostic score identified three groups of patients with distinctly different risk profiles with median OS estimated at 16.2, 9.2, and 4.5 months. We demonstrated the additional prognostic value of HRQoL in UGB for death risk stratification and provided a score that may help to guide clinical management and stratification in future clinical trials.
Human epidermal growth factor receptor 2-positive breast cancer is a subtype of interest regarding its outcome and the impressive impact of human epidermal growth factor receptor 2 targeted therapy. ...Constitutional variants may be involved in the aetiology of human epidermal growth factor receptor 2-positive breast cancer, and we propose a case-case study to test the hypothesis that single nucleotide polymorphisms may be associated with human epidermal growth factor receptor 2 status. A Genome-Wide Association Study was used in a cohort of 9836 patients from the SIGNAL/PHARE study (NCT00381901-RECF1098). The main goal was to identify variants specifically related to human epidermal growth factor receptor 2-positive breast cancer. A two-staged genotyping strategy was carried out to cover as large a proportion of the genome as possible. All subjects were genotyped using the Illumina HumanCore Exome chip set. Principal Components Analysis and
-means were then used to characterize the ancestry of the participants. A random sample of subjects from the main "European" cluster was genotyped with the Omni5 chip set. These data were then used to impute missing genotypes from the remaining subjects genotyped only using the HumanCore Exome array. From the 9836 patients, a total of 8703 cases including 3230 patients with human epidermal growth factor receptor 2-positive breast cancer were analyzed. Despite having 80% power to detect an odds ratio of 1.23 in this population, no variant achieved genome-wide significance for association with the occurrence of human epidermal growth factor receptor 2-positive breast cancer vs. any other subtype of breast tumour. Our study was unable to identify constitutional polymorphisms that are strongly associated with human epidermal growth factor receptor 2-positive status among breast cancer patients.
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