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Personalized targeted therapy for lung cancer.

Wu K, House L, Liu W, Cho WC - Int J Mol Sci (2012)

Bottom Line: Personalized medicine refers to the use of markers to predict which patient will most likely benefit from a treatment.In lung cancer, the well-developed epidermal growth factor receptor (EGFR) and the newly emerging EML4-anaplastic lymphoma kinase (ALK) are important therapeutic targets.Nevertheless, it is foreseeable that the sequencing and systems strategies may offer a solution for those patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA; E-Mails: kwu@bsd.uchicago.edu (K.W.); lhouse@medicine.bsd.uchicago.edu (L.H.).

ABSTRACT
Lung cancer has long been recognized as an extremely heterogeneous disease, since its development is unique in every patient in terms of clinical characterizations, prognosis, response and tolerance to treatment. Personalized medicine refers to the use of markers to predict which patient will most likely benefit from a treatment. In lung cancer, the well-developed epidermal growth factor receptor (EGFR) and the newly emerging EML4-anaplastic lymphoma kinase (ALK) are important therapeutic targets. This review covers the basic mechanism of EGFR and EML4-ALK activation, the predictive biomarkers, the mechanism of resistance, and the current targeted tyrosine kinase inhibitors. The efficacy of EGFR and ALK targeted therapies will be discussed in this review by summarizing the prospective clinical trials, which were performed in biomarker-based selected patients. In addition, the revolutionary sequencing and systems strategies will also be included in this review since these technologies will provide a comprehensive understanding in the molecular characterization of cancer, allow better stratification of patients for the most appropriate targeted therapies, eventually resulting in a more promising personalized treatment. The relatively low incidence of EGFR and ALK in non-Asian patients and the lack of response in mutant patients limit the application of the therapies targeting EGFR or ALK. Nevertheless, it is foreseeable that the sequencing and systems strategies may offer a solution for those patients.

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Related in: MedlinePlus

The frequency of EGFR mutations. The deletion of exon 19 nested located between residues 747–750, which are mainly composed of delGlu746-Ala750, delGlu746-Ser752insVal, delLeu747-Thr751, delLeu747-Ser752, and delLeu747-Pro753insSer.
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f2-ijms-13-11471: The frequency of EGFR mutations. The deletion of exon 19 nested located between residues 747–750, which are mainly composed of delGlu746-Ala750, delGlu746-Ser752insVal, delLeu747-Thr751, delLeu747-Ser752, and delLeu747-Pro753insSer.

Mentions: Potent response predictors are necessary to help doctors predict which patients will most likely to respond to EGFR TKIs. These predictors are ultimately used to obtain an optimal treatment while avoiding resistance. In 2004, three influential studies discovered a series of somatic mutations in the kinase domain of EGFR which are associated with the response to EGFR TKI therapy [23–25]. To date, EGFR mutations are presumed to be the strongest predictive biomarker for the efficacy of EGFR TKI therapy [26] due to much higher response rate (RR, 37.5%–100% vs. 2.9%–23% [27]; 70% vs. 33.2% as a first-line treatment; 47.4% vs. 28.5% as a second-line treatment [28]) and longer overall survival (OS, 13–23 months vs. 5–17 months [27]) in mutant patients. Mok [29] summarized six clinical trials to compare the response to EGFR TKIs and chemotherapy in patients carrying positive mutations. Patients have responded better to EGFR TKIs than to chemotherapy demonstrated by a higher RR (62.1%–84.6% vs. 10.5%–47.3%) and longer progression-free survival (PFS) (8.4–13.1 months vs. 4.6–6.7 months). In April 2011, the American Society of Clinical Oncology (ASCO) has issued a provisional clinical opinion, which suggested that initiating first-line therapy with an EGFR TKI should be based on positive EGFR mutation tests in patients with newly diagnosed advanced NSCLC [30]. EGFR mutations are more common in non-smoking East Asian females and those with adenocarcinoma histology (95% were found in adenocarcinomas) [31–36]. There are several reviews summarizing the frequency and distribution of EGFR mutations (Figure 2) [14,15,29,33,37–39].


Personalized targeted therapy for lung cancer.

Wu K, House L, Liu W, Cho WC - Int J Mol Sci (2012)

The frequency of EGFR mutations. The deletion of exon 19 nested located between residues 747–750, which are mainly composed of delGlu746-Ala750, delGlu746-Ser752insVal, delLeu747-Thr751, delLeu747-Ser752, and delLeu747-Pro753insSer.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3472758&req=5

f2-ijms-13-11471: The frequency of EGFR mutations. The deletion of exon 19 nested located between residues 747–750, which are mainly composed of delGlu746-Ala750, delGlu746-Ser752insVal, delLeu747-Thr751, delLeu747-Ser752, and delLeu747-Pro753insSer.
Mentions: Potent response predictors are necessary to help doctors predict which patients will most likely to respond to EGFR TKIs. These predictors are ultimately used to obtain an optimal treatment while avoiding resistance. In 2004, three influential studies discovered a series of somatic mutations in the kinase domain of EGFR which are associated with the response to EGFR TKI therapy [23–25]. To date, EGFR mutations are presumed to be the strongest predictive biomarker for the efficacy of EGFR TKI therapy [26] due to much higher response rate (RR, 37.5%–100% vs. 2.9%–23% [27]; 70% vs. 33.2% as a first-line treatment; 47.4% vs. 28.5% as a second-line treatment [28]) and longer overall survival (OS, 13–23 months vs. 5–17 months [27]) in mutant patients. Mok [29] summarized six clinical trials to compare the response to EGFR TKIs and chemotherapy in patients carrying positive mutations. Patients have responded better to EGFR TKIs than to chemotherapy demonstrated by a higher RR (62.1%–84.6% vs. 10.5%–47.3%) and longer progression-free survival (PFS) (8.4–13.1 months vs. 4.6–6.7 months). In April 2011, the American Society of Clinical Oncology (ASCO) has issued a provisional clinical opinion, which suggested that initiating first-line therapy with an EGFR TKI should be based on positive EGFR mutation tests in patients with newly diagnosed advanced NSCLC [30]. EGFR mutations are more common in non-smoking East Asian females and those with adenocarcinoma histology (95% were found in adenocarcinomas) [31–36]. There are several reviews summarizing the frequency and distribution of EGFR mutations (Figure 2) [14,15,29,33,37–39].

Bottom Line: Personalized medicine refers to the use of markers to predict which patient will most likely benefit from a treatment.In lung cancer, the well-developed epidermal growth factor receptor (EGFR) and the newly emerging EML4-anaplastic lymphoma kinase (ALK) are important therapeutic targets.Nevertheless, it is foreseeable that the sequencing and systems strategies may offer a solution for those patients.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Chicago, Chicago, IL 60637, USA; E-Mails: kwu@bsd.uchicago.edu (K.W.); lhouse@medicine.bsd.uchicago.edu (L.H.).

ABSTRACT
Lung cancer has long been recognized as an extremely heterogeneous disease, since its development is unique in every patient in terms of clinical characterizations, prognosis, response and tolerance to treatment. Personalized medicine refers to the use of markers to predict which patient will most likely benefit from a treatment. In lung cancer, the well-developed epidermal growth factor receptor (EGFR) and the newly emerging EML4-anaplastic lymphoma kinase (ALK) are important therapeutic targets. This review covers the basic mechanism of EGFR and EML4-ALK activation, the predictive biomarkers, the mechanism of resistance, and the current targeted tyrosine kinase inhibitors. The efficacy of EGFR and ALK targeted therapies will be discussed in this review by summarizing the prospective clinical trials, which were performed in biomarker-based selected patients. In addition, the revolutionary sequencing and systems strategies will also be included in this review since these technologies will provide a comprehensive understanding in the molecular characterization of cancer, allow better stratification of patients for the most appropriate targeted therapies, eventually resulting in a more promising personalized treatment. The relatively low incidence of EGFR and ALK in non-Asian patients and the lack of response in mutant patients limit the application of the therapies targeting EGFR or ALK. Nevertheless, it is foreseeable that the sequencing and systems strategies may offer a solution for those patients.

Show MeSH
Related in: MedlinePlus