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The EGFR mutation status affects the relative biological effectiveness of carbon-ion beams in non-small cell lung carcinoma cells.

ABSTRACT: Carbon-ion radiotherapy (CIRT) holds promise to treat inoperable locally-advanced non-small cell lung carcinoma (NSCLC), a disease poorly controlled by standard chemoradiotherapy using X-rays. Since CIRT is an extremely limited medical resource, selection of NSCLC patients likely to benefit from it is important; however, biological predictors of response to CIRT are ill-defined. The present study investigated the association between the mutational status of EGFR and KRAS, driver genes frequently mutated in NSCLC, and the relative biological effectiveness (RBE) of carbon-ion beams over X-rays. The assessment of 15 NSCLC lines of different EGFR/KRAS mutational status and that of isogenic NSCLC lines expressing wild-type or mutant EGFR revealed that EGFR-mutant NSCLC cells, but not KRAS-mutant cells, show low RBE. This was attributable to (i) the high X-ray sensitivity of EGFR-mutant cells, since EGFR mutation is associated with a defect in non-homologous end joining, a major pathway for DNA double-strand break (DSB) repair, and (ii) the strong cell-killing effect of carbon-ion beams due to poor repair of carbon-ion beam-induced DSBs regardless of EGFR mutation status. These data highlight the potential of EGFR mutation status as a predictor of response to CIRT, i.e., CIRT may show a high therapeutic index in EGFR mutation-negative NSCLC.

SUBMITTER: Amornwichet N

PROVIDER: S-EPMC4463964 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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The EGFR mutation status affects the relative biological effectiveness of carbon-ion beams in non-small cell lung carcinoma cells.

Amornwichet Napapat N Oike Takahiro T Shibata Atsushi A Nirodi Chaitanya S CS Ogiwara Hideaki H Makino Haruhiko H Kimura Yuka Y Hirota Yuka Y Isono Mayu M Yoshida Yukari Y Ohno Tatsuya T Kohno Takashi T Nakano Takashi T

Scientific reports 20150611

Carbon-ion radiotherapy (CIRT) holds promise to treat inoperable locally-advanced non-small cell lung carcinoma (NSCLC), a disease poorly controlled by standard chemoradiotherapy using X-rays. Since CIRT is an extremely limited medical resource, selection of NSCLC patients likely to benefit from it is important; however, biological predictors of response to CIRT are ill-defined. The present study investigated the association between the mutational status of EGFR and KRAS, driver genes frequently ...[more]

PMID: 26065573

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Project description:Background and purposeCarbon ion radiation therapy (CIRT) is recognized as an effective alternative treatment modality for early stage lung cancer, but a quantitative understanding of relative biological effectiveness (RBE) compared to photon therapy is lacking. In this work, a mechanistic tumor response model previously validated for lung photon radiotherapy was used to estimate the RBE of CIRT compared to photon radiotherapy, as a function of dose and the fractionation schedule.Materials and methodsClinical outcome data of 9 patient cohorts (394 patients) treated with CIRT for early stage lung cancer, representing all published data, were included. Fractional dose, number of fractions, treatment schedule, and local control rates were used for model simulations relative to standard photon outcomes. Four parameters were fitted: α, α/β, and the oxygen enhancement ratios of cells either accessing only glucose, not oxygen (OERI), or cells dying from starvation (OERH). The resulting dose-response relationship of CIRT was compared with the previously determined dose-response relationship of photon radiotherapy for lung cancer, and an RBE of CIRT was derived.ResultsBest-fit CIRT parameters were: α = 1.12 Gy-1 [95%-CI: 0.97-1.26], α/β = 23.9 Gy [95%-CI: 8.9-38.9], and the oxygen induced radioresistance of hypoxic cell populations were characterized by OERI = 1.08 [95%-CI: 1.00-1.41] (cells lacking oxygen but not glucose), and OERH = 1.01 [95%-CI: 1.00-1.44] (cells lacking oxygen and glucose). Depending on dose and fractionation, the derived RBE ranges from 2.1 to 1.5, with decreasing values for larger fractional dose and fewer number of fractions.ConclusionFitted radiobiological parameters were consistent with known carbon in vitro radiobiology, and the resulting dose-response curve well-fitted the reported data over a wide range of dose-fractionation schemes. The same model, with only a few fitted parameters of clear mechanistic meaning, thus synthesizes both photon radiotherapy and CIRT clinical experience with early stage lung tumors.

Project description:Purpose: To perform a prospective study to evaluate the efficacy and safety of isolated recurrent tumor re-irradiation with carbon-ion radiotherapy (RT). Methods and Materials: The inclusion criteria were clinically proven recurrent tumors, measurable by computed tomography or magnetic resonance imaging, patients ≥ 16 years old, performance status scores between 0 and 2, isolated tumor at a previously irradiated site, and a life expectancy > 6 months. The exclusion criteria were tumor invasion into the gastrointestinal tract or a major blood vessel, uncontrolled infection, early recurrence (<3 months), and severe concomitant diseases. The primary end-point was the local control rate, the secondary end-points including the overall survival rate, and adverse events. Results: Between December 2013 and March 2016, 22 patients were enrolled in this prospective study. All patients were re-irradiated with carbon-ion RT with radical intent. Five patients had rectal cancer, 4 had sarcoma, 4 had lung cancer, 3 had hepatic cell carcinoma, and 6 had other tumors. The median follow-up time was 26 months. Eight patients developed local recurrence, and the 1- and 2-year local control rates were 71 and 60%, respectively. Eight patients died of their cancers and 2 died of other diseases. The 1- and 2-year overall survival rates were 76 and 67%, respectively. There were no grade 2 or higher acute adverse events and 4 patients (18%) developed grade 3 late adverse events. The group with the longer interval (>16 months) between the first RT and re-irradiation had significantly better outcomes than the shorter interval group (≤ 16 months). Conclusions: Re-irradiation, using carbon-ion RT with radical intent, had favorable local control and overall survival rates without severe toxicities for selected patients. Re-irradiation has the potential to improve clinical outcomes for isolated, local, recurrent tumors; further investigations are required to confirm the therapeutic efficacy.

Project description:BackgroundHelium (4He) ion beam therapy provides favorable biophysical characteristics compared to currently administered particle therapies, i.e., reduced lateral scattering and enhanced biological damage to deep-seated tumors like heavier ions, while simultaneously lessened particle fragmentation in distal healthy tissues as observed with lighter protons. Despite these biophysical advantages, raster-scanning 4He ion therapy remains poorly explored e.g., clinical translational is hampered by the lack of reliable and robust estimation of physical and radiobiological uncertainties. Therefore, prior to the upcoming 4He ion therapy program at the Heidelberg Ion-beam Therapy Center (HIT), we aimed to characterize the biophysical phenomena of 4He ion beams and various aspects of the associated models for clinical integration.MethodsCharacterization of biological effect for 4He ion beams was performed in both homogenous and patient-like treatment scenarios using innovative models for estimation of relative biological effectiveness (RBE) in silico and their experimental validation using clonogenic cell survival as the gold-standard surrogate. Towards translation of RBE models in patients, the first GPU-based treatment planning system (non-commercial) for raster-scanning 4He ion beams was devised in-house (FRoG).ResultsOur data indicate clinically relevant uncertainty of ±5-10% across different model simulations, highlighting their distinct biological and computational methodologies. The in vitro surrogate for highly radio-resistant tissues presented large RBE variability and uncertainty within the clinical dose range.ConclusionsExisting phenomenological and mechanistic/biophysical models were successfully integrated and validated in both Monte Carlo and GPU-accelerated analytical platforms against in vitro experiments, and tested using pristine peaks and clinical fields in highly radio-resistant tissues where models exhibit the greatest RBE uncertainty. Together, these efforts mark an important step towards clinical translation of raster-scanning 4He ion beam therapy to the clinic.

Dataset Information

The EGFR mutation status affects the relative biological effectiveness of carbon-ion beams in non-small cell lung carcinoma cells.

Publications

The EGFR mutation status affects the relative biological effectiveness of carbon-ion beams in non-small cell lung carcinoma cells.

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