KRAS Mutation is Associated with Decreased Overall Survival after Thoracic Radiation Therapy in Patients with Locally Advanced Non-small Cell Lung Cancer

Mak, Raymond H.; Doran, Elizabeth; Muzikansky, Alona; Neal, Joel W.; Baldini, Elizabeth H.; Choi, Noah C.; Willers, Henning; Jackman, David M.; Sequist, Lecia V.

doi:10.1016/j.ijrobp.2010.07.121

Cited by 3 publications

(2 citation statements)

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“…For example, experimental data indicate that mutations in EGFR impair NHEJ and increase cellular radiosensitivity, and clinical observations are consistent with improved local tumor control for EGFR mutant NSCLC treated with radiation 44,98 . Conversely, it has been suggested that mutant KRAS promotes cellular radioresistance by promoting NHEJ, though whether KRAS mutant NSCLC are more radioresistant than KRAS wild-type cancers remains to be established 99,100 . Mutations in the ATM kinase, which controls aspects of NHEJ, occurs in ~7% of lung adenocarcinoma 51,101 .…”

Section: Dna Double-strand Breaks and Damage-based Therapiesmentioning

confidence: 99%

Basic Mechanisms of Therapeutic Resistance to Radiation and Chemotherapy in Lung Cancer

Willers¹,

Azzoli²,

Santivasi³

et al. 2013

The Cancer Journal

171

138

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In recent years, there have been multiple breakthroughs in our understanding of lung cancer biology. Despite significant advances in molecular targeted therapies DNA-damaging cytotoxic therapies will remain the mainstay of lung cancer management for the foreseeable future. Similar to the concept of personalized targeted therapies there is mounting evidence that perturbations in DNA repair pathways are common in lung cancers, altering the resistance of the affected tumors to many chemotherapeutics as well as radiation. Defects in DNA repair may be due to a multitude of mechanisms including gene mutations, epigenetic events, and alterations in signal transduction pathways such as EGFR and PI3K/AKT. Functional biomarkers that assess the subcellular localization of central repair proteins in response to DNA damage may prove useful for individualization of cytotoxic therapies including PARP inhibitors. A better mechanistic understanding of cellular sensitivity and resistance to DNA damaging agents should facilitate the development of novel, individualized treatment approaches. Absolute resistance to radiation therapy, however, does not exist. To some extent, radiation therapy will always have to remain unselective and indiscriminant to eradicate persistent, drug-resistant tumor stem cell pools.

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Section: Dna Double-strand Breaks and Damage-based Therapiesmentioning

confidence: 99%

Basic Mechanisms of Therapeutic Resistance to Radiation and Chemotherapy in Lung Cancer

Willers¹,

Azzoli²,

Santivasi³

et al. 2013

The Cancer Journal

171

138

View full text Add to dashboard Cite

show abstract

“…For example, retrospective series have demonstrated that patients with locally advanced EGFR mutant NSCLC had lower risk of locoregional failure compared to EGFR wild-type (WT) patients after chemotherapy and conventional RT, 18–20 while patients with KRAS- mutant locally advanced NSCLC had decreased OS compared to those with KRAS WT tumors. 19 However, it remains unclear if differences in radiation response by genotype is relevant at the higher doses delivered with SBRT.…”

Section: Introductionmentioning

confidence: 99%

Outcomes by Tumor Histology and KRAS Mutation Status After Lung Stereotactic Body Radiation Therapy for Early-Stage Non–Small-Cell Lung Cancer

Mak

Hermann

Lewis

et al. 2015

Clinical Lung Cancer

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We analyzed outcomes after lung stereotactic body radiotherapy (SBRT) for early-stage non–small-cell lung carcinoma in patients by histology and KRAS mutation status. Histology was not associated with outcomes, but KRAS mutation was associated with lower freedom from recurrence on univariable analysis and decreased cancer-specific survival on multivariable analysis. Given the small sample sizes, these results are hypothesis generating, and further study of SBRT outcomes by tumor genotype in larger data sets is needed. Background We analyzed outcomes after lung stereotactic body radiotherapy (SBRT) for early-stage non–small cell lung-carcinoma (NSCLC) by histology and KRAS genotype. Patients and Methods We included 75 patients with 79 peripheral tumors treated with SBRT (18 Gy × 3 or 10 to 12 Gy × 5) at our institution from 2009 to 2012. Genotyping for KRAS mutations was performed in 10 patients. Outcomes were analyzed by the Kaplan-Meier method/Cox regression, or cumulative incidence method/Fine-Gray analysis. Results The median patient age was 74 (range, 46 to 93) years, and Eastern Cooperative Oncology Group performance status was 0 to 1 in 63%. Tumor histology included adenocarcinoma (44%), squamous cell carcinoma (25%), and NSCLC (18%). Most tumors were T1a (54%). Seven patients had KRAS-mutant tumors (9%). With a median follow-up of 18.8 months among survivors, the 1-year estimate of overall survival was 88%, cancer-specific survival (CSS) 92%, primary tumor control 94%, and freedom from recurrence (FFR) 67%. In patients with KRAS-mutant tumors, there was a significantly lower tumor control (67% vs. 96%; P = .04), FFR (48% vs. 69%; P = .03), and CSS (75% vs. 93%; P = .05). On multivariable analysis, histology was not associated with outcomes, but KRAS mutation (hazard ratio, 10.3; 95% confidence interval, 2.3–45.6; P = .0022) was associated with decreased CSS after adjusting for age. Conclusion In this SBRT series, histology was not associated with outcomes, but KRAS mutation was associated with lower FFR on univariable analysis and decreased CSS on multivariable analysis. Because of the small sample size, these hypothesis-generating results need to be studied in larger data sets.

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Outcomes by EGFR, KRAS, and ALK Genotype After Combined Modality Therapy for Locally Advanced Non–Small-Cell Lung Cancer

Mak

Hermann

Aerts

et al. 2018

JCO Precision Oncology

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Purpose In 699 patients with locally advanced non–small-cell lung cancer (NSCLC) treated with radiation therapy as part of combined modality therapy, we compared outcomes among genotyped and ungenotyped patients and by tumor genotype status ( EGFR, KRAS, and ALK). Patients and Methods Genotyping was performed in 250 patients: EGFR+ (19%), KRAS+ (32%), ALK+ (9%), and wild type (WT−/−/−; 40%). Outcomes were analyzed using the Kaplan-Meier method and Cox regression. Results With a median follow-up of 48.2 months among genotyped patients, median overall survival (OS) was significantly longer for EGFR+ and ALK+ compared with KRAS+ and WT−/−/− (55.8 months v not reached v 28.0 v 33.2 months; P = .02). There was no difference in progression-free survival (median, 15.3 v 13.7 v 13.0 v 14.5 months; P = .47) or in freedom from distant metastases by genotype (3-year estimates: 42% v 49% v 27% v 25%; P = .25). There was higher freedom from locoregional recurrence (LRR) for EGFR+ tumors and lower freedom from LRR in ALK+ tumors, compared with KRAS+ and WT−/−/− tumors (3-year: 77% v 38% v 49% v 46%). In multivariable analysis, ALK+ remained associated with increased OS (HR, 0.32; 95% CI, 0.12 to 0.87; P = .03), and EGFR+ was associated with decreased LRR (HR, 0.47; 95% CI, 0.24 to 0.92; P = .03). Analysis of post-recurrence survival demonstrated that EGFR+/ ALK+ patients treated with appropriate tyrosine kinase inhibitors had higher OS compared with other groups. Conclusion In this series of locally advanced NSCLC treated with combined modality therapy, EGFR+ and ALK+ were associated with higher OS, whereas LRR was lower in EGFR+ patients, and the risk of distant metastases was high in all subgroups. The outcomes and patterns of failure in genotypic subgroups of NSCLC from this study can inform the design of future trials integrating targeted therapies.

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KRAS Mutation is Associated with Decreased Overall Survival after Thoracic Radiation Therapy in Patients with Locally Advanced Non-small Cell Lung Cancer

Cited by 3 publications

References 0 publications

Basic Mechanisms of Therapeutic Resistance to Radiation and Chemotherapy in Lung Cancer

Basic Mechanisms of Therapeutic Resistance to Radiation and Chemotherapy in Lung Cancer

Outcomes by Tumor Histology and KRAS Mutation Status After Lung Stereotactic Body Radiation Therapy for Early-Stage Non–Small-Cell Lung Cancer

Outcomes by EGFR, KRAS, and ALK Genotype After Combined Modality Therapy for Locally Advanced Non–Small-Cell Lung Cancer

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