Next‐generation sequencing and clinical outcomes of patients with lung adenocarcinoma treated with stereotactic body radiotherapy

Cassidy, Richard J.; Zhang, Xinyan; Patel, Pretesh; Shelton, Joseph; Escott, C.; Sica, Gabriel L.; Rossi, Michael R.; Hill, Charles E.; Steuer, Conor E.; Pillai, Rathi N.; Ramalingam, Suresh S.; Owonikoko, Taofeek K.; Behera, Madhusmita; Force, Seth D.; Fernández, Félix G.; Higgins, Kristin

doi:10.1002/cncr.30794

Cited by 38 publications

(37 citation statements)

References 42 publications

(110 reference statements)

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“…Radiotherapy is considered the cornerstone treatment in NSCLC patients who present with BM; however, response rates range widely, and we currently lack predictive tools to assess which patients will most benefit from this intervention . Interestingly, genetic aberrations are well characterized within the advanced‐stage NSCLC population . The impact of these genetic aberrations in terms of patient outcomes has been extensively studied for systemic interventions.…”

Section: Discussionmentioning

confidence: 99%

“…For example, EGFR ‐mutated patients included in the IPASS study had better response to targeted therapy with gefitinib compared to wild‐type EGFR patients (71.2% vs. 1.1%), but also had a higher response to taxane‐based chemotherapy schemes (47.3% vs. 23.5%, respectively), highlighting the differential tumor biology between these molecular subtypes and its impact on clinical outcomes . However, the genetic profile is not currently taken into consideration in order to drive radiotherapy recommendations …”

Section: Discussionmentioning

confidence: 99%

“…However, both these retrospective analyses included patients who had received previous systemic therapy, and therefore the impact of the molecular feature on the radiological outcome might be confounded. The impact of other genetic alterations ‐ such as ALKr and KRAS mutations ( KRAS m) ‐ in the treatment with RT as well as survival in NSCLC patients with BM has been mostly unexplored; however, a recent report in early‐stage lung adenocarcinoma found that KRAS mutations were associated with worse local control in patients treated with stereotactic body radiotherapy (SBRT) …”

Section: Introductionmentioning

confidence: 99%

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Response rate of patients with baseline brain metastases from recently diagnosed non‐small cell lung cancer receiving radiotherapy according to EGFR, ALK and KRAS mutation status

et al. 2020

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Background Previous studies have identified that patients with EGFR mutations tend to have better responses to targeted therapy, as well as chemotherapy; however, the effect of genetic alterations in terms of radiotherapy (RT)‐related outcomes has not been fully assessed. We studied the impact of common non‐small cell lung cancer (NSCLC) genetic alterations (EGFR, ALK and KRAS) in relation to objective response rate (ORR) to RT in patients with brain metastases. Methods From 2009–2015, 153 patients with an available genotyping status were treated with whole‐brain irradiation (WBI) before receiving systemic therapy. Primary outcome was ORR; secondary outcomes included intracranial progression‐free survival (IPFS) and overall survival (OS). Results Overall, ORR was 47.1%. ORR to RT varied significantly according to molecular status: EGFR (64.5%) ALK (54.5%) KRAS (20%) and WT (35.4%) (P = 0.001). EGFR mutation was the only independently associated factor for response to WBI (RR 3.52 [95% CI 1.6–7.7]; P = 0.002). Median IPFS was 10.8 months [95% CI 8.2–13.5] overall; however, IPFS also varied significantly according to molecular status: EGFR (18.2 months), ALK (18.4 months), KRAS (6.0 months) and WT (8.7 months) (P < 0.0001). OS for EGFR, ALK, KRAS and WT patients was 36.6, 32.2, 15.5 and 22.4 months, respectively (P = 0.014). Intracranial‐ORR (HR 0.4 [95% CI 0.2–0.6], P < 0.001) and mutation status (HR 0.7 [95% CI 0.6–0.9], P < 0.042) were independently associated with a higher OS. Conclusions RT response varies as per tumor molecular status. The presence of EGFR mutations favors the organ‐specific response to RT, and is associated with longer OS in patients with NSCLC and BM. Key points This study addressed for the first time the difference in radiotherapy‐related outcomes in patients with different genotypes of non‐small cell lung cancer (NSCLC) before they received systemic therapy. Results show that response to radiotherapy varies as per tumor molecular status, particularly EGFR‐mutated tumors, have a favorable response to radiotherapy, contrary to KRAS‐mutated tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Response rate of patients with baseline brain metastases from recently diagnosed non‐small cell lung cancer receiving radiotherapy according to EGFR, ALK and KRAS mutation status

et al. 2020

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“…Given these concerns regarding aggressive chemoradiation in an elderly population, targeted agents and immunotherapy also play a role in therapy. Although typically reserved for patients with metastatic disease, recent reports have indicated that the incidence of molecular mutations appears congruent between patients with early‐stage and late‐stage disease . In addition, there are ongoing clinical trials examining the impact of targeted agents and/or immunotherapy in the upfront nonmetastatic setting .…”

Section: Discussionmentioning

confidence: 99%

“…Although typically reserved for patients with metastatic disease, recent reports have indicated that the incidence of molecular mutations appears congruent between patients with early-stage and late-stage disease. [22][23][24][25] In addition, there are ongoing clinical trials examining the impact of targeted agents and/or immunotherapy in the upfront nonmetastatic setting. [26][27][28] Depending on these outcomes, these agents would be useful in an elderly population because their side effect profile generally is more favorable than that of traditional cytotoxic chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Health care disparities among octogenarians and nonagenarians with stage III lung cancer

Cassidy

Zhang

Switchenko

et al. 2018

Cancer

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Radioresistance of KRAS/TP53‐mutated lung cancer can be overcome by radiation dose escalation or EGFR tyrosine kinase inhibition in vivo

Gurtner

Kryzmien

Koi

et al. 2019

Intl Journal of Cancer

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Recent clinical data have linked KRAS/TP53 comutation (mut) to resistance to radiotherapy (RT), but supporting laboratory in vivo evidence is lacking. In addition, the ability of different radiation doses, with/without epidermal growth factor receptor (EGFR)-directed treatment, to achieve local tumor control as a function of KRAS status is unknown. Here, we assessed clonogenic radiation survival of a panel of annotated lung cancer cell lines. KRASmut/TP53mut was associated with the highest *H.W., M.B. and M.K. shared co-senior authorship Additional Supporting Information may be found in the online version of this article. Molecular Cancer Biologyradioresistance in nonisogenic and isogenic comparisons. To validate these findings, isogenic TP53mut NCI-H1703 models, KRASmut or wild-type (wt), were grown as heterotopic xenografts in nude mice. A clinical RT schedule of 30 fractions over 6 weeks was employed. The dose that controlled 50% of tumors (TCD 50 ) was calculated. The TCD 50 for KRASwt/TP53mut xenografts was 43.1 Gy whereas KRASmut/TP53mut tumors required a 1.9-fold higher TCD 50 of 81.4 Gy. The EGFR inhibitor erlotinib radiosensitized KRASmut but not KRASwt cells and xenografts. The TCD 50 associated with adding erlotinib to RT was 58.8 Gy for KRASmut, that is, a~1.4-fold dose enhancement. However, the EGFR antibody cetuximab did not have a radiosensitizing effect. In conclusion, we demonstrate for the first time that KRASmut in a TP53mut background confers radioresistance when studying a clinical RT schedule and local control rather than tumor growth delay. Despite the known unresponsiveness of KRASmut tumors to EGFR inhibitors, erlotinib radiosensitized KRASmut tumors. Our data highlight KRAS/TP53 comutation as a candidate biomarker of radioresistance that can be at least partially reversed by dose escalation or the addition of a targeted agent. What's new?Clinical data linked co-mutation of the KRAS GTPase and the p53 tumor suppressor to radioresistance but rigorous pre-clinical studies have not been conducted. Here the authors validated these studies in mice and found that for local control of co-mutated non-small cell lung carcinoma xenografts an approximately two-fold higher dose of radiotherapy was required compared to wild-type tumors. Interestingly, pharmacological inhibition of epidermal growth factor receptor signaling sensitized co-mutated tumors to radiotherapy, underscoring the validity of the genotype as biomarker with therapeutic consequences.

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Next‐generation sequencing and clinical outcomes of patients with lung adenocarcinoma treated with stereotactic body radiotherapy

Cited by 38 publications

References 42 publications

Response rate of patients with baseline brain metastases from recently diagnosed non‐small cell lung cancer receiving radiotherapy according to EGFR, ALK and KRAS mutation status

Response rate of patients with baseline brain metastases from recently diagnosed non‐small cell lung cancer receiving radiotherapy according to EGFR, ALK and KRAS mutation status

Health care disparities among octogenarians and nonagenarians with stage III lung cancer

Radioresistance of KRAS/TP53‐mutated lung cancer can be overcome by radiation dose escalation or EGFR tyrosine kinase inhibition in vivo

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