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  #11  
Old 09-13-2015, 06:41 PM
gdpawel gdpawel is offline
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Default Targeted Therapy Based on Tumor Molecular Profiling May Not Improve Survival

The use of molecularly targeted agents outside of their indications did not improve progression-free survival compared with physician treatment of choice in heavily pretreated patients with cancer, according to an online article published online ahead of print in The Lancet Oncology.1

Increased off-label use of molecular agents in patients whose tumors harbor the matching molecular alterations has been reported. Investigators performed a study to assess the efficacy of several molecularly targeted agents, which were chosen on the basis of molecular profiling but used outside of their indications in patients with advanced cancer for whom standard-of-care therapy had failed.

A total of 741 patients with any tumor type were screened, and 293 (40%) had at least one molecular alteration matching one of the 10 available regimens.

At the time of data cutoff, 195 patients had been randomly assigned to the experimental group (n=99) and 96 in the control group. Median follow up was 11.3 months (IQR 5.8-11.6) in the experimental group and 11.3 months (IQR 8.1-11.6) in the control group at the time of primary progression-free survival analysis.

Median progression-free survival was 2.3 months (95% CI: 1.7-3.8) in the experimental group versus 2.0 months (95% CI: 1.8-2.1) in the control group (HR 0.88; 95% CI: 0.65-1.19; P=0.41).

In the safety population, 43% of 100 patients treated with a molecularly targeted agent and 35% of 91 patients of 91 patients treated with cytotoxic chemotherapy experienced grade 3-4 adverse events (P=0.30).

The investigators concluded that “Off-label use of molecularly targeted agents should be discouraged, but enrollment in clinical trials should be encouraged to assess predictive biomarkers of efficacy.

Reference

Le Tourneau C, Delord J-P, Gavoille C, et al. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. [published online ahead of print September 2, 2015]. Lancet Oncol. doi: 10.1016/S1470-2045(15)00188-6.
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  #12  
Old 10-02-2015, 12:42 AM
gdpawel gdpawel is offline
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Default Molecularly targeted therapies chosen based on tumor profiling did not improve PFS

Molecularly Targeted Therapy vs Conventional Therapy for Advanced Cancer

ABSTRACT

BACKGROUND

Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed.

METHODS

The open-label, randomised, controlled phase 2 SHIVA trial was done at eight French academic centres. We included adult patients with any kind of metastatic solid tumour refractory to standard of care, provided they had an Eastern Cooperative Oncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection of a metastatic site, and at least one measurable lesion. The molecular profile of each patient's tumour was established with a mandatory biopsy of a metastatic tumour and large-scale genomic testing. We only included patients for whom a molecular alteration was identified within one of three molecular pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK), which could be matched to one of ten regimens including 11 available molecularly targeted agents (erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen). We randomly assigned these patients (1:1) to receive a matched molecularly targeted agent (experimental group) or treatment at physician's choice (control group) by central block randomisation (blocks of size six). Randomisation was done centrally with a web-based response system and was stratified according to the Royal Marsden Hospital prognostic score (0 or 1 vs 2 or 3) and the altered molecular pathway. Clinicians and patients were not masked to treatment allocation. Treatments in both groups were given in accordance with the approved product information and standard practice protocols at each institution and were continued until evidence of disease progression. The primary endpoint was progression-free survival in the intention-to-treat population, which was not assessed by independent central review. We assessed safety in any patients who received at least one dose of their assigned treatment.

FINDINGS

Between Oct 4, 2012, and July 11, 2014, we screened 741 patients with any tumour type. 293 (40%) patients had at least one molecular alteration matching one of the 10 available regimens. At the time of data cutoff, Jan 20, 2015, 195 (26%) patients had been randomly assigned, with 99 in the experimental group and 96 in the control group. All patients in the experimental group started treatment, as did 92 in the control group. Two patients in the control group received a molecularly targeted agent: both were included in their assigned group for efficacy analyses, the patient who received an agent that was allowed in the experimental group was included in the experimental group for the purposes of safety analyses, while the other patient, who received a molecularly targeted agent and chemotherapy, was kept in the control group for safety analyses. Median follow-up was 11·3 months (IQR 5·8–11·6) in the experimental group and 11·3 months (8·1–11·6) in the control group at the time of the primary analysis of progression-free survival. Median progression-free survival was 2·3 months (95% CI 1·7–3·8) in the experimental group versus 2·0 months (1·8–2·1) in the control group (hazard ratio 0·88, 95% CI 0·65–1·19, p=0·41). In the safety population, 43 (43%) of 100 patients treated with a molecularly targeted agent and 32 (35%) of 91 patients treated with cytotoxic chemotherapy had grade 3–4 adverse events (p=0·30).

INTERPRETATION

The use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at physician's choice in heavily pretreated patients with cancer. Off-label use of molecularly targeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assess predictive biomarkers of efficacy.

The Lancet Oncology

Molecularly Targeted Therapy Based on Tumour Molecular Profiling Versus Conventional Therapy for Advanced Cancer (SHIVA): A Multicentre, Open-Label, Proof-of-Concept, Randomised, Controlled Phase 2 Trial

Lancet Oncol 2015 Sep 02;[EPub Ahead of Print], CL Tourneau, JP Delord, A Gonçalves, C Gavoille, C Dubot, N Isambert, M Campone, O Trédan, MA Massiani, C Mauborgne, S Armanet, N Servant, I Bièche, V Bernard, D Gentien, P Jezequel, V Attignon, S Boyault, A Vincent-Salomon, V Servois, MP Sablin, M Kamal, X Paoletti

[url]http://www.ncbi.nlm.nih.gov/pubmed/26342236
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  #13  
Old 11-18-2015, 08:01 PM
gdpawel gdpawel is offline
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Default Gene Study of Liver Tumor Reveals Versatile DNA

Tumors may have much greater genetic versatility than previously thought, and researchers say that might explain their ability to resist cancer treatments.

The finding comes from extensive and rigorous genetic sequencing carried out on a single tumor.

The human liver tumor that the scientists studied -- which was slightly more than 1 inch in diameter -- contained more than 100 million distinct mutations within the coding regions of its genes. That's thousands of times more than what scientists expected.

"With 100 million mutations, each capable of altering a protein in some way, there is a high probability that a significant minority of tumor cells will survive, even after aggressive treatment," study director Chung-I Wu, a professor of ecology and evolution at the University of Chicago, said in a university news release.

The study was published in the issue of the Proceedings of the National Academy of Sciences.

The results suggest that even tiny tumors are likely to have extremely high genetic diversity, and to have cells that may be able to resist standard postsurgical chemotherapy and radiation, the researchers said.

"In a setting with so much diversity, those cells could multiply to form new tumors, which would be resistant to standard treatments," Wu explained.
Previous research has shown that cancer patients' chances of survival decrease as genetic diversity within tumors increases, because more mutations make drug resistance more likely.

"The possibility of high intra-tumor diversity even in small tumors suggests a need to re-evaluate treatment strategies," the study authors concluded.

Source: University of Chicago, news release, Nov. 9, 2015
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