Personalizing Radiotherapy Prescription Dose Using Genomic Markers of Radiosensitivity and Normal Tissue Toxicity in NSCLC

Scott, Jacob G.; Sedor, Geoffrey; Scarborough, Jessica; Kattan, Michael W.; Peacock, Jeffrey; Grass, G. Daniel; Mellon, Eric A.; Thapa, Ram; Schell, Michael J.; Waller, Anthony F.; Poppen, S.; Andl, George; Teer, Jamie K.; Eschrich, Steven A.; Dilling, Thomas J.; Dalton, William S.; Harrison, Louis B.; Fox, Tim; Torres-Roca, Javier F.

doi:10.1016/j.jtho.2020.11.008

Cited by 37 publications

(24 citation statements)

References 44 publications

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“…These data suggest that local-regional control can be substantially affected independent of radiation dosing. Furthermore, although there has been a greater understanding in how tumor and host genetic factors affect radiation sensitivity, 23,24 the impact of durvalumab should also be computed in future strategies personalizing radiation dose. Moreover, the striking impact of durvalumab on local-regional control found herein suggests that one potential underlying mechanism by which durvalumab improves patient survival is through its direct actions on local-regional disease.…”

Section: Discussionmentioning

confidence: 99%

“…Overall, this study provides the most robust data to date on the impact of durvalumab on local-regional disease outcomes and in KEAP1-NFE2L2-mutant tumors. With a growing understanding of both the toxicity of radiotherapy on thoracic organs and the heterogeneity of radiation sensitivity among tumors and patients, 24,29,30 appreciating the role of durvalumab on local-regional control can aide future trial development investigating radiation dose and volume personalization in stage III NSCLC.…”

Section: Discussionmentioning

confidence: 99%

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The Impact of Durvalumab on Local-Regional Control in Stage III NSCLCs Treated With Chemoradiation and on KEAP1-NFE2L2-Mutant Tumors

Shaverdian

Offin

Shepherd

et al. 2021

Journal of Thoracic Oncology

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Introduction: KEAP1-NFE2L2-mutant NSCLCs are chemoradiation resistant and at high risk for local-regional failure (LRF) after concurrent chemoradiation (cCRT). To elucidate the impact of durvalumab on local-regional control, we evaluated LRF in patients with NSCLC treated with cCRT with and without durvalumab.Methods: Patients with stage III NSCLC treated with cCRT or cCRT and durvalumab who underwent tumor genomic profiling were evaluated. The incidence of LRF and outcomes of patients with and without KEAP1-NFE2L2-mutant tumors were evaluated.Results: We analyzed 120 consecutive patients (cCRT alone, n ¼ 54; cCRT and durvalumab, n ¼ 66). Patients treated with cCRT alone had significantly more LRF events compared with those treated with cCRT and durvalumab, with 12-month LRF incidence of 39% (95% confidence interval [CI]: 24%-54%) and 18% (95% CI: 8%-28%), respectively (p ¼ 0.002). Among patients treated with cCRT alone and cCRT and durvalumab, 20 patients (37%) and 18 patients (27%), respectively, had KEAP1-NFE2L2mutant tumors. In patients treated with cCRT alone, those with KEAP1-NFE2L2-mutant tumors had worse localregional control (p ¼ 0.015), and on multivariate analysis, KEAP1-NFE2L2 mutation predicted for LRF (hazard ratio ¼ 3.9, 95% CI: 1.6-9.8, p ¼ 0.003). Nevertheless, patients with and without KEAP1-NFE2L2-mutant tumors had similar LRF outcomes (p ¼ 0.541) when treated with cCRT and durvalumab, and mutational status did not predict for LRF (p ¼ 0.545). Among those with KEAP1-NFE2L2-mutant tumors, cCRT and durvalumab significantly reduced the incidence of LRF compared with cCRT alone: 12-month LRF incidence of 62% (95% CI: 40%-*Corresponding author. Disclosure: Dr. Shaverdian reports receiving research funding from Novartis. Dr. Offin reports having advisory role for PharMar, Novartis, and Targeted Oncology and receiving honoraria from Bristol-Myers Squibb and Merck Sharp & Dohme. Dr. Shepherd reports receiving honoraria from ASCO. Dr. Simone II reports receiving honoraria from Varian Medical Systems. Dr. Wu reports receiving research support from CivaTech Oncology, Inc., nonfinancial support from AlphaTau Medical, personal fees from MoreHealth, and personal fees from AstraZeneca. Dr. Hellmann reports receiving personal fees from Genentech, Mirati, Syndax, Nektar, Blueprint Medicines, and Merck; grants, personal fees, and nonfinancial support from Bristol-Myers Squibb; personal fees and nonfinancial support from AstraZeneca; and personal fees and equity from Shattuck Labs and Immunai;

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Impact of Durvalumab on Local-Regional Control in Stage III NSCLCs Treated With Chemoradiation and on KEAP1-NFE2L2-Mutant Tumors

Shaverdian

Offin

Shepherd

et al. 2021

Journal of Thoracic Oncology

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“…Despite several obstacles, biology-based personalization is being slowly incorporated in the field of RT, 43 and a very recent study showed that such an approach may be also useful in term of NTCP predictions. 44 Instead of gene signatures, we decided to evaluate circulating miRNAs, which posttranscriptionally regulate gene expression. Currently, these molecules have not been investigated in the context of radiation-induced xerostomia.…”

Section: Discussionmentioning

confidence: 99%

Serum MicroRNAs as Xerostomia Biomarkers in Patients With Oropharyngeal Cancer Undergoing Radiation Therapy

Tomasik

Papis-Ubych

Stawiski

et al. 2021

International Journal of Radiation Oncology*Biology*Physics

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Severe xerostomia is noted in the majority of patients irradiated for oropharyngeal cancer. Extracellular microRNAs (miRNAs) may serve as effective tools allowing prediction of radiation-related toxicity. The aim of this study was to create an efficient prognostic miRNA-based test for severe, patient-rated xerostomia 3 months after primary treatment. Methods and Materials: This prospective study enrolled patients with oropharyngeal cancer treated between 2016 and 2018 in 3 centers in Poland. The primary endpoint was severe (grade ≥3) xerostomia as assessed by the European Organisation for

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“…A Comissão de Oncologia Lancet identificou GARD como um candidato a biomarcador por personalizar a radioterapia, e a Organização Europeia de Pesquisa e Tratamento do Câncer identificou os dados apresentados de RSI/GARD como uma prioridade em estudos de fase 3 (SCOTT et al, 2021).…”

Section: Dose De Radiação Genomicamente Ajustada (Gard)unclassified

“…em 50, 60 e 70 Gy (Gray) foram determinadas na década de 60 com base nos modelos de probabilidade de controle tumoral (TCP)(SCOTT et al, 2021). Esses protocolos variam de acordo com o sítio e a histologia tumoral, porém eles não avaliam diferenças biológicas individuais de radiossensibilidade da região que será irradiada (células tumorais e sadias) do paciente para cada tipo de câncer (AZRIA,ROSENSTEIN, 2020).O sequenciamento do genoma humano abriu caminho para uma nova era de precisão na medicina, a qual visa que o tratamento certo será entregue ao paciente certo no momento certo.…”

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A utilização da dose de radiação genomicamente ajustada (gard) para tratamento de câncer de mama triplo-negativo – uma revisāo da literatura / The use of the genomically adjusted radiation dose (gard) for treatment of triple-negative breast cancer – a literature review

Severiano¹,

Rückel²,

Prevedello³

et al. 2021

Braz. J. Hea. Rev.

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Personalizing Radiotherapy Prescription Dose Using Genomic Markers of Radiosensitivity and Normal Tissue Toxicity in NSCLC

Cited by 37 publications

References 44 publications

The Impact of Durvalumab on Local-Regional Control in Stage III NSCLCs Treated With Chemoradiation and on KEAP1-NFE2L2-Mutant Tumors

The Impact of Durvalumab on Local-Regional Control in Stage III NSCLCs Treated With Chemoradiation and on KEAP1-NFE2L2-Mutant Tumors

Serum MicroRNAs as Xerostomia Biomarkers in Patients With Oropharyngeal Cancer Undergoing Radiation Therapy

A utilização da dose de radiação genomicamente ajustada (gard) para tratamento de câncer de mama triplo-negativo – uma revisāo da literatura / The use of the genomically adjusted radiation dose (gard) for treatment of triple-negative breast cancer – a literature review

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