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Detection of EGFR gene mutations in non-small cell lung cancer: Lessons from a single-institution routine analysis of 1,403 tumor samples.

Detection of EGFR gene mutations in non-small cell lung cancer: Lessons from a single-institution routine analysis of 1,403 tumor samples.

Int J Oncol. 2013 Aug 7;

Authors: Vallee A, Sagan C, Le Loupp AG, Bach K, Dejoie T, Denis MG

Abstract
Activating mutations of the epidermal growth factor receptor (EGFR) in lung tumors are associated with a dramatic response to tyrosine kinase inhibitors. Therefore, routine analysis of pathological specimens is mandatory in clinical practice. We have prospectively tested tumors from Caucasian lung tumor patients between January 2010 and June 2012. DNA was extracted from formalin-fixed paraffin-embedded tissues following macrodissection. The p.L858R substitution was assessed by allele-specific PCR and exon 19 deletions by PCR and DNA fragment analysis. Using a robust process from patient sampling to screening methods, we analyzed samples from 1,403 patients. The EGFR status could be successfully determined for 1,322 patients. EGFR mutations were detected in 179 (13.5%) patients, with female and adenocarcinoma histology predominance. Mutated patients were significantly older than non‑mutated patients. Similar mutation rates were obtained with primary tumors and metastases, and with surgical resection, bronchial biopsies, CT-guided needle biopsies and transbronchial needle aspiration. The sensitivity of our assays allowed us to detect EGFR mutations in samples poor (<10%) in tumor cells. Finally, the mutation rate was much higher in tumors expressing the TTF-1 antigen (145/820; 17.7%) than in TTF-1 negative tumors (3/218; 1.4%). The results obtained through routine analysis of more than 1,300 samples indicated that all types of specimen can be analyzed without any significant bias. TTF-1 immunostaining may be used to predict negative EGFR mutation status.

PMID: 23934203 [PubMed - as supplied by publisher]

Managing brain metastases patientswith and without radiotherapy: initial lessonsfrom a team-based consult service through a multidisciplinary integrated palliative oncology clinic.

Managing brain metastases patientswith and without radiotherapy: initial lessonsfrom a team-based consult service through a multidisciplinary integrated palliative oncology clinic.

Support Care Cancer. 2013 Aug 10;

Authors: Jung H, Sinnarajah A, Enns B, Voroney JP, Murray A, Pelletier G, Wu JS

Abstract
PURPOSE: A new ambulatory consultative clinic with integrated assessments by palliative care, radiation oncology, and allied health professionals was introduced to (1) assess patients with brain metastases at a regional comprehensive cancer center and (2) inform and guide patients on management strategies, including palliative radiotherapy, symptom control, and end-of-life care issues. We conducted a quality assurance study to inform clinical program development.
METHODS: Between January 2011 and May 2012, 100 consecutive brain metastases patients referred and assessed through a multidisciplinary clinic were evaluated for baseline characteristics, radiotherapy use, and supportive care decisions. Overall survival was examined by known prognostic groups. Proportion of patients receiving end-of-life radiotherapy (death within 30 and 14 days of brain radiotherapy) was used as a quality metric.
RESULTS: The median age was 65 years, with non-small cell lung cancer (n = 38) and breast cancer (n = 23) being the most common primary cancers. At least 57 patients were engaged in advance care planning discussions at first consult visit. In total, 75 patients eventually underwent brain radiotherapy, whereas 25 did not. The most common reasons for nonradiotherapy management were patient preference and rapid clinical deterioration. Overall survival for prognostic subgroups was consistent with literature reports. End-of-life brain radiotherapy was observed in 9 % (death within 30 days) and 1 % (within 14 days) of treated patients.
CONCLUSIONS: By integrating palliative care expertise to address the complex needs of patients with newly diagnosed brain metastases, end-of-life radiotherapy use appears acceptable and improved over historical rates at our institution. An appreciable proportion of patients are not suitable for palliative brain radiotherapy or opt against this treatment option, but the team approach involving nurses, palliative care experts, allied health, and clinical oncologists facilitates patient-centered decision making and transition to end-of-life care.

PMID: 23934224 [PubMed - as supplied by publisher]

Molecular and cytogenetic changes in multi-drug resistant cancer cells and their influence on new compounds testing.

Molecular and cytogenetic changes in multi-drug resistant cancer cells and their influence on new compounds testing.

Cancer Chemother Pharmacol. 2013 Aug 10;

Authors: Podolski-Renić A, Jadranin M, Stanković T, Banković J, Stojković S, Chiourea M, Aljančić I, Vajs V, Tešević V, Ruždijić S, Gagos S, Tanić N, Pešić M

Abstract
PURPOSE: Multi-drug resistance (MDR) is a major obstacle to successful cancer treatment. Therefore, in vitro models are necessary for the investigation of the phenotypic changes provoked by cytotoxic agents and more importantly for preclinical testing of new anticancer drugs.
METHODS: We analyzed chromosomal, numerical, and structural changes after development of MDR, alterations in p53 and PTEN, single nucleotide polymorphisms (SNPs) in the mdr1 gene and corresponding protein expression of P-glycoprotein (P-gp) in three human MDR cancer cell lines: non-small cell lung carcinoma NCI-H460/R, colorectal carcinoma DLD1-TxR, and glioma U87-TxR. In addition, we explored how these molecular and phenotypic alterations influence the anticancer effect of new drugs.
RESULTS: Cytogenetic analysis showed polyploidy reduction after development of MDR in U87-TxR. Losses of 6q in all resistant cancer cell lines and inactivation of p53 in U87-TxR and PTEN in DLD1-TxR were also revealed. Overexpression of P-gp was observed in all MDR cancer cell lines. We evaluated the anticancer activities and MDR reversal potential of Akt inhibitor GSK690693, Ras inhibitor Tipifarnib, and two P-gp inhibitors (jatrophane diterpenoids). Their effects vary due to the cell-type differences, existence of MDR phenotype, presence of mdr1 SNP, and tumor suppressors' alterations. Tipifarnib and jatrophane diterpenoids significantly sensitized MDR cancer cells to paclitaxel.
CONCLUSION: In conclusion, investigated MDR cancer cells obtained new molecular and cytogenetic characteristics that may serve as potential clinical prognostic markers. In addition, these MDR cancer cell lines present a valuable model for preclinical evaluation of new anticancer agents.

PMID: 23934261 [PubMed - as supplied by publisher]

Targeting the Immune System in the Treatment of Non-Small-Cell Lung Cancer.

Targeting the Immune System in the Treatment of Non-Small-Cell Lung Cancer.

Curr Treat Options Oncol. 2013 Aug 11;

Authors: Rangachari D, Brahmer JR

Abstract
OPINION STATEMENT: Non-small-cell lung cancer (NSCLC) remains the most common cause of cancer-related death worldwide. Traditional cytotoxic agents and their attendant toxicities have remained the mainstay of systemic therapy for this disease, until now. With the identification of novel molecular and immune cancer-specific aberrancies, molecular agents and immunotherapies have garnered increasing attention as attractive targets, with the potential for improved outcomes while mitigating systemic toxicities seen with traditional cytotoxic agents. Despite a longstanding interest in immunotherapy for the treatment of NSCLC, results of prior studies of therapeutic vaccines have failed to show durable or convincingly meaningful clinical responses. However, newer trials of therapeutic vaccines and checkpoint inhibitors have yielded more promising results. In particular, the checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed death-1 (PD-1) pathway have shown meaningful clinical responses with manageable toxicities. Large phase III studies are underway, the results of which have the potential to revolutionize the way in which we care for patients with NSCLC. More studies also are needed to investigate the potentially synergistic effects of traditional and immune-based therapies. Given their unique antineoplastic effects, novel immune-specific clinical endpoints also are actively being investigated.

PMID: 23934510 [PubMed - as supplied by publisher]

A Rational Diagnostic Algorithm for the Identification of ALK Rearrangement in Lung Cancer: A Comprehensive Study of Surgically Treated Japanese Patients.

EML4-ALK fusion gene is found in only a small subset (2-6%) of non-small cell lung cancer. There is an urgent need to establish a rational diagnostic algorithm to identify this rare but important fusion in lung cancer.

METHODS: We performed a comprehensive analysis of EGFR/KRAS mutation and ALK rearrangement in a total of 360 surgically resected lung cancers. ALK rearrangement was examined by 3 analyses: multiplex reverse transcription-PCR, fluorescent in situ hybridization (FISH), and immunohistochemistry (IHC) with the intercalated antibody-enhanced polymer method. A scoring system was used for IHC (iScore). A test set (202 patients with unselected lung cancer) was used for proposing a diagnostic algorithm. This diagnostic algorithm was validated in 158 patients with EGFR and KRAS mutation-negative adenocarcinoma.

RESULTS: ALK rearrangement was identified in 2 patients (1.0%) from the test set and both adenocarcinomas were negative for EGFR and KRAS mutations. The results of FISH and RT-PCR were completely matched. The highest iScore 3 was found only in the 2 positive cases. A diagnostic algorithm was proposed: IHC screening for ALK rearrangement followed by confirmatory FISH. In the validation set, 8 cases (5.1%) had iScore 3 and were positive for FISH, while the other cases had iScore 0 and were negative for FISH.

CONCLUSIONS: Screening for ALK rearrangement by IHC followed by confirmatory FISH is a rational diagnostic algorithm. If needed, patients may be selected for screening ALK rearrangement by their EGFR and KRAS mutation status.

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