Mutational profiles of primary pulmonary adenocarcinoma and paired brain metastases disclose the importance of KRAS mutations

Abstract BACKGROUND Immunotherapy is increasingly used in patients with non-small cell lung cancer brain metastases (NSCLCBM). KRAS mutations are associated with worse prognosis and there is no FDA approved targeted therapy. KRAS mutations are associated with increased expression of PD-L1. We evaluated the outcomes of NSCLCBM with KRAS mutations treated with immune checkpoint inhibitors (ICI). METHODS We reviewed 800 patients with NSCLCBM treated at our tertiary care center. 226 had known KRAS mutational status, 121 of which received immunotherapy. Overall survival (OS) was calculated from either the start of immunotherapy (when both groups received immunotherapy) or from the date of diagnosis of brain metastasis. Kaplan-Meier method and Cox Proportional hazard model were utilized to determine differences in OS and the Chi-square test was utilized to determine differences in PD-L1 expression. RESULTS In 109 patients where both KRAS and PD-L1 status were known, KRAS mutations had greater PD-L1 expression (80.1% vs 61.9% positive, p=0.04). There was no difference in OS between KRAS mutant vs KRAS wild-type patients treated with immunotherapy. Median survival from the start of immunotherapy was 15.6 vs 15.5 months respectively (p=0.7), after adjusting for age, KPS, lesion number and extra-cranial metastasis (HR = .91, p=.7). Patients with KRAS mutations treated with immunotherapy versus those who received chemotherapy had a 1-year OS from the diagnosis of brain metastasis of 60.9% vs 38.7% respectively (trending towards significance, p=0.05). KRAS wild-type patients treated with immunotherapy versus those who did not receive immunotherapy had a 1-year OS from the diagnosis of brain metastasis of 61.9% vs 62.5% (p=0.85), respectively. DISCUSSION KRAS mutations are associated with increased PD-L1 expression. Use of immunotherapy negates the poor outcomes seen traditionally in patients with NSCLCBM and KRAS mutations and it improves survival compared to use of chemotherapy. Our experience supports the use of immunotherapy in these patients.

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Salvage Therapy of Pembrolizumab and Bevacizumab in a Case of Advanced Pulmonary Adenocarcinoma With Multiple Brain Metastases

American Journal of Therapeutics ◽

10.1097/mjt.0000000000001221 ◽

2020 ◽

Vol Publish Ahead of Print ◽

Author(s):

Chang-Guo Wang ◽

Chao Liu ◽

Chen Chen ◽

Da-Xiong Zeng ◽

Jian-An Huang

Keyword(s):

Brain Metastases ◽

Salvage Therapy ◽

Pulmonary Adenocarcinoma ◽

Multiple Brain Metastases

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Presence of genetic aberrations in patients with brain metastases from non-small cell lung cancer (NSCLC) and clinical outcomes.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e20604 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e20604-e20604 ◽

Cited By ~ 1

Author(s):

Robert H. Press ◽

Xinyan Zhang ◽

Richard John Cassidy ◽

Matthew Jeffrey Ferris ◽

Jim Zhong ◽

...

Keyword(s):

Lung Cancer ◽

Targeted Therapy ◽

Brain Metastases ◽

Clinical Outcomes ◽

Performance Status ◽

Multivariable Analysis ◽

Genetic Alterations ◽

Kras Mutations ◽

Brain Radiotherapy ◽

Systemic Therapies

e20604 Background: Historically, survival in patients (pts) with NSCLC brain metastases (BM) is poor, however, improved systemic therapies are now available including targeted therapies and immunotherapy. We sought to evaluate the prevalence of genetic alterations in pts with BM from non-squamous (NS) lung cancer, and to determine clinical outcomes in the modern era. Methods: With IRB approval, pts with BM from NS-NSCLC from 1/2010-1/2016 with genetic testing were captured and retrospectively reviewed. Snapshot genotyping was performed prior to 1/2014, after which Next Generation Sequencing was utilized, along with FISH lung cancer panel. Genes examined included: EGFR, ALK, RET, ROS1, TP53, KRAS, NRAS, MET, PTEN, BRAF, FBXW7, MAP2K1, APC, PIK3CA, CTNNB1, and SMAD4. Univariable and multivariable analysis (MVA) were utilized to assess factors associated with overall survival (OS). Results: 92 pts were included. Median number of BM was 4 (range 1-45). Median age was 64 (32-90 years). 59.8% were male. 38% received targeted therapy, 11% received immunotherapy, and 70% received conventional chemotherapy. 52.2% and 47.8% received whole brain radiotherapy and stereotactic radiosurgery, respectively. Median OS from first brain radiotherapy (RT) was 10.7 months (0.1-56.4). EGFR mutation, ALK fusion, ROS1 rearrangement, and RET rearrangement occurred in 27.5%, 5.2%, 1.7%, and 0% of pts. EGFR L858 and EGFR T790 mutations occurred in 19.2% and 2.7% of all pts. TP53, KRAS, and NRAS mutations occurred in 63.9%, 28.8% and 7% of pts. All other mutations had an incidence of less than 3%. On MVA, targeted therapy (HR 0.43 95% CI 0.22-0.86), immunotherapy (HR 0.04 95% CI 0.01-0.3), surgical resection (HR 0.38 95% CI 0.18-0.81), and ECOG performance status (0.23 95% CI 0.1-0.54) were associated with improved OS. No specific genetic aberration, RT modality, or number of BM was associated with OS. Conclusions: In pts with BM from NS-NSCLC, the most common molecular aberrations include TP53, EGFR, and KRAS mutations. Treatment with brain RT and modern systemic therapies yields a median survival greater than ten months. The use of targeted therapy or immunotherapy was associated with increased OS.

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Outcomes of KRAS mutated, EGFR mutated, ALK mutated and wildtype patients in non-small cell lung cancer brain metastases.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21028 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21028-e21028

Author(s):

Yasmeen Rauf ◽

Vineeth Tatineni ◽

Patrick joseph Oshea ◽

Xuefei Jia ◽

David M. Peereboom ◽

...

Keyword(s):

Lung Cancer ◽

Retrospective Study ◽

Brain Metastases ◽

Targeted Therapies ◽

Small Cell ◽

Egfr Mutations ◽

Small Cell Lung ◽

Kras Mutations ◽

Alk Positive ◽

Egfr Mutated

e21028 Background: Non-small cell lung cancer (NSCLC) is the most common primary tumor leading to brain metastases. Multiple genetic markers have been profiled in NSCLC patients for potential targeted therapies. EGFR is mutated in up 50% of NSCLCs, while ALK is mutated in around 4-7%. KRAS is the most commonly overexpressed marker, seen in up to 85% of all lung cancers. In this retrospective study, we evaluated the overall survival (OS) and progression-free survival (PFS) between NSCLCBM patients with KRAS mutations, ALK mutations, EGFR mutations, and wildtype. Methods: NSCLCBM patients diagnosed between 2010 and 2019 were analyzed. We collected information regarding molecular marker status, systemic therapies, and date of progression. We defined OS as the date of diagnosis of brain metastases to the date of last follow-up or death. OS and PFS were estimated by the Cox proportional model. Results: We found a total of 2989 NCSLCBM patients, 184 were KRAS mutated, 68 had an ALK gene rearrangement, 184 were EGFR mutated, and 1469 were wildtype. The respective median age was 64.3 years, 64.5 years, 58.2 years, and 64.2 years. Females made up 61.8% of KRAS-positive, 51.8% of ALK-positive, 63% of EGFR-positive, and 46.4% of wildtype patients. The median OS (mOS) in patients who were KRAS-positive, ALK-positive, EGFR-positive, and wildtype were 43.3 months, 119.2 months, 57.9 months, and 33.1 months, respectively. The median PFS (mPFS) for the same cohort was 38.0 months, 112.4 months, 55.3 months, and 30.5 months, respectively. ALK-positive patients showed statistically significant mOS (p-value (p) < 0.001) and mPFS (p = 0.002) when compared to EGFR-positive, KRAS-positive, and wildtype patients. Conclusions: Molecular mutations serve as both prognostic predictors and alternative targeted therapies for NSCLCBM treatment. Our retrospective study showed improved mOS and mPFS in NSCLCBM patients with ALK rearrangements when compared to patients with EGFR mutations, KRAS mutations, and the wildtype. While these results looked at patient outcomes with specific tumor markers, further investigation needs to be done regarding outcomes of specific therapies in each cohort, as well as, intracranial lesion response.

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EGFR and KRAS Mutations Predict the Incidence and Outcome of Brain Metastases in Non-Small Cell Lung Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms17122132 ◽

2016 ◽

Vol 17 (12) ◽

pp. 2132 ◽

Cited By ~ 24

Author(s):

Pascale Tomasini ◽

Cindy Serdjebi ◽

Nataliya Khobta ◽

Philippe Metellus ◽

L’Houcine Ouafik ◽

...

Keyword(s):

Lung Cancer ◽

Brain Metastases ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Kras Mutations

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Enrichment of Met Amplification and Kras Mutations in Non-Small Cell Lung Carcinoma (NSCLC) Brain Metastases

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2014.08.212 ◽

2014 ◽

Vol 90 (5) ◽

pp. S35-S36

Author(s):

L.C. Villaruz ◽

M.A. Socinski ◽

V. Derrick ◽

S.A. Bartoluzzi ◽

B. Kurland ◽

...

Keyword(s):

Brain Metastases ◽

Lung Carcinoma ◽

Small Cell Lung Carcinoma ◽

Small Cell ◽

Small Cell Lung ◽

Kras Mutations ◽

Cell Lung Carcinoma ◽

Met Amplification

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Early-stage KRAS G12C-mutated non-small cell lung cancer (NSCLC) in Australia.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21053 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21053-e21053

Author(s):

Paul Mitchell ◽

Devisri Dharmaraj ◽

Simon Knight

Keyword(s):

Lung Cancer ◽

Brain Metastases ◽

Recurrent Disease ◽

Early Stage ◽

Kras Mutations ◽

Curative Intent ◽

Failure Data ◽

Initial Recurrence ◽

Austin Health ◽

Almost All

e21053 Background: KRAS is frequently mutated in NSCLC, especially in Caucasian populations. Until recently there have not been effective targeted therapies against KRAS but the recent advent of active agents has thrown a spotlight on this disease. Methods: A database of NSCLC cases undergoing lobectomy or pneumonectomy with curative intent at Austin Health, Victoria, Australia was examined. Analysis for KRAS mutations was carried out using the LungCarta panel. Results: Four hundred and fifty nine cases underwent mutation analysis and 203/459 (44%) were wild type. KRAS mutations were identified in 100/459 cases (21.8%), including 3 cases where the specific mutation was not specified. KRAS G12C cases comprised 40/97 (8.5% of all cases, 41% of specified mutation KRAS cases) and other KRAS mutations comprised 57/97 (59%) - most commonly G12V (25 cases) and G12D (13 cases). Additional mutations were identified in 14/40 (36%) G12C mutation cases (10 dual and 4 triple – most commonly TP53 9, STK11 3 and PIC3CA 2). In non-G12C cases, multiple mutations were identified in 24% of cases. Considering the 40 G12C cases, histology was squamous cell in 21 cases, adenocarcinoma 13 and other 5. Males comprised 21/40 cases, median age at diagnosis was 61 year (range 34 – 78), with stage I 22 cases, stage II 12; stage IIIA 5 and one stage 4 (solitary brain metastasis). Thirty six patients (90%) had smoked tobacco with median exposure of 44 pack years (range 13-100) including 18 ex-smokers who had ceased a median 9 years (range 1 - 28) prior to the diagnosis of lung cancer. PD-L1 expression was analysed using the 28-8 antibody. For the 38 cases analysed, PD-L1 expression was ≥ 50% in 6 (16%), ≥ 5% in 12 (32%) and < 1% in 24 (63%). The estimated median overall survival was 4.9 years with 27% 10 year survival. Twenty three patients (58%) died from the index lung cancer, 8 (20%) remain alive and 9 (23%) died of other causes: 4 from a 2nd lung cancer, 4 from a non-lung cancer and one from liver failure. Data on sites of recurrence were available for 16 of the 23 cases who died from the index lung cancer, with initial recurrence sites being lung/local 7 patients, brain 6, bone 2, liver 1. A total of 9 patients (56%) developed brain metastases at some time. Conclusions: KRAS G12C is a common subgroup of NSCLC in the Australian population and almost all of cases were tobacco smokers. Additional mutations were identified in over a third of cases. Locally recurrent disease or brain metastases are the most frequent sites of relapse and over half of patients with recurrent disease develop brain metastases.

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THER-09. IMPACT OF KRAS MUTATION STATUS ON THE EFFICACY OF IMMUNOTHERAPY IN LUNG CANCER BRAIN METASTASES

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz014.052 ◽

2019 ◽

Vol 1 (Supplement_1) ◽

pp. i12-i12

Author(s):

Adam Lauko ◽

Assad Ali ◽

Soumya Sagar ◽

Addison Barnett ◽

Hong Li ◽

...

Keyword(s):

Lung Cancer ◽

Brain Metastasis ◽

Brain Metastases ◽

Checkpoint Inhibitors ◽

Care Center ◽

Tertiary Care ◽

Wild Type ◽

Chi Square ◽

Kras Mutations ◽

Mutational Status

Abstract BACKGROUND: Immunotherapy is increasingly used in patients with non-small cell lung cancer brain metastases (NSCLCBM). KRAS mutations are associated with worse prognosis and there is no FDA approved targeted therapy. KRAS mutations are associated with increased expression of PD-L1. We evaluated the outcomes of NSCLCBM with KRAS mutations treated with immune checkpoint inhibitors (ICI). METHODS: We reviewed 800 patients with NSCLCBM treated at our tertiary care center. 226 had known KRAS mutational status, 121 of which received immunotherapy. Overall survival (OS) was calculated from either the start of immunotherapy (when both groups received immunotherapy) or from the date of diagnosis of brain metastasis. Kaplan-Meier method and Cox Proportional hazard model were utilized to determine differences in OS and the Chi-square test was utilized to determine differences in PD-L1 expression. RESULTS: In 109 patients where both KRAS and PD-L1 status were known, KRAS mutations had greater PD-L1 expression (80.1% vs 61.9% positive, p=0.04). There was no difference in OS between KRAS mutant vs KRAS wild-type patients treated with immunotherapy. Median survival from the start of immunotherapy was 15.6 vs 15.5 months respectively (p=0.7), after adjusting for age, KPS, lesion number and extra-cranial metastasis (HR = .91, p=.7). Patients with KRAS mutations treated with immunotherapy versus those who received chemotherapy had a 1-year OS from the diagnosis of brain metastasis of 60.9% vs 38.7% respectively (trending towards significance, p=0.05). KRAS wild-type patients treated with immunotherapy versus those who did not receive immunotherapy had a 1-year OS from the diagnosis of brain metastasis of 61.9% vs 62.5% (p=0.85), respectively. DISCUSSION: KRAS mutations are associated with increased PD-L1 expression. Use of immunotherapy negates the poor outcomes seen traditionally in patients with NSCLCBM and KRAS mutations and it improves survival compared to use of chemotherapy. Our experience supports the use of immunotherapy in these patients.

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Healing efficacy in lung adenocarcinoma after targeted therapy, Covid 19 disease and radiosurgery of brain metastasеs

Medical & Clinical Research ◽

10.33140/mcr.06.030 ◽

2021 ◽

Vol 6 ◽

Keyword(s):

Targeted Therapy ◽

Brain Metastases ◽

Lung Adenocarcinoma ◽

Pulmonary Adenocarcinoma ◽

Egfr Mutations ◽

Common Disease ◽

Shortness Of Breath ◽

Men And Women ◽

Local Progression ◽

Metastatic Lung

Lung adenocarcinoma is a common disease, in which high mortality is due to both men and women. In the article we present a 58-year-old man who has been diagnosed with metastatic pulmonary adenocarcinoma/T2B N2 M1a in 2018, on the occasion of dry irritating cough and shortness of breath. Also a positive EGFR mutations has been proven. Targeted therapy (TT) with gefitinib has been carried out for two years till 2020. The patient has been switched on osimertinib in 2020 due to local progression. Brain metastasis has been found in 2021. Radiosurgery (RS) with a singal fraction 15Gy was conducted for treatment of 4 brain metastases . The patient was infected after RS with Covid 19 in April 2021. Patients with specific EGFR mutations can be effectively treated with TT. After treatment with TT, brain metastases of pulmonary adenocarcinoma with specific EGFR mutations are more radiоsensibility and responded very well by high single radiation dose realized by radiosurgery (RS). Despite the worsened prognosis, including Covid 19 disease, by combining TT and RS, we achieved three-year survival in metastatic lung adenocarcinoma.

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