Somatic mutations of EGFR and KRAS in pure bronchioloalveolar carcinomas and adenocarcinomas of the lung with bronchioloalveolar features

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21111-21111
Author(s):  
I. J. Dahabreh ◽  
S. Murray ◽  
H. T. Spiliadi ◽  
E. A. Karagiani ◽  
A. Stamatelopoulos ◽  
...  
Keyword(s):  
Egfr Inhibitors ◽  
Egfr Mutations ◽  
Kras Mutations ◽  
Cell Content ◽  
Clinicopathologic Factor ◽  
Exon 2 ◽  
Asian Ethnicity ◽  
Lung Cancers ◽  
Egfr Expression ◽  
Clinicopathologic Parameters

21111 Background: EGFR mutations are more common in lung cancers from female, non-smoking patients of Asian ethnicity with adenocarcinoma histology. We investigated the relationship between clinicopathologic parameters and mutations of EGFR and KRAS in patients with pure bronchioloalveolar carcinomas (BACs) and adenocarcinomas (ADCs) with BAC features, not previously treated with EGFR inhibitors. Methods: We retrospectively reviewed the files of patients who were diagnosed with pure BACs or ADCs with BAC features between February 2001 and May 2005. Demographics, stage and smoking histories were recorded. Paraffin embedded tissue blocks were retrieved and re-examined using the WHO 1999/2004 histological criteria for lung cancers. EGFR expression, detected by immunohistochemistry, was scored from 0 to +3. Expression was considered positive when the score was +1, or higher. DNA was isolated from paraffin blocks (containing at least 75% tumor cell content) and exons 18–21 of the EGFR gene and exon 2 of the KRAS gene were amplified by PCR and bi-directionally sequenced. The chi-squared test and regression analysis were used to identify parameters correlating with EGFR or KRAS mutations. Results: A total of 46 patients were eligible for this study. Tissue was available from 43 patients, 19 with pure BAC and 24 with ADC with BAC features. There were 27 (62.8%) males and 16 (37.2%) females, all of Greek descent. Mean age was 62.7 years (range, 41–79). There were 34 smokers and former smokers (79%) and 9 never-smokers (21%). Tumors were classified as mucinous (20), non- mucinous (19) or mixed (4). We detected somatic EGFR mutations in 7 patients (including common mutations, delEx19, L858R, G719C), and KRAS codon 12 mutations in 13 patients. EGFR and KRAS mutations were mutually exclusive. No clinicopathologic parameters correlated with the presence of EGFR or KRAS mutations. Conclusions: Among Greek lung cancer patients with pure BACs or ADCs with BAC features, unselected for response to EGFR inhibitors, the incidence of KRAS or EGFR mutations was 30.2% and 16.3% respectively. EGFR and KRAS mutations were mutually exclusive but no clinicopathologic factor predicted the presence of mutations in either gene. Further molecular analysis is ongoing. No significant financial relationships to disclose.

Drug Combinatorial Therapies for the Treatment of KRAS Mutated Lung Cancers

2019 ◽  
Vol 19 (23) ◽  
pp. 2128-2142 ◽  
Author(s):  
Hao He ◽  
Chang Xu ◽  
Zhao Cheng ◽  
Xiaoying Qian ◽  
Lei Zheng
Keyword(s):  
Lung Cancer ◽  
Adjuvant Therapy ◽  
Combination Therapy ◽  
Clinical Benefit ◽  
Poor Prognosis ◽  
Egfr Mutations ◽  
Kras Mutations ◽  
Lung Cancers ◽  
Egfr Tki ◽  
Egfr Tkis

: KRAS is the most common oncogene to be mutated in lung cancer, and therapeutics directly targeting KRAS have proven to be challenging. The mutations of KRAS are associated with poor prognosis, and resistance to both adjuvant therapy and targeted EGFR TKI. EGFR TKIs provide significant clinical benefit for patients whose tumors bear EGFR mutations. However, tumors with KRAS mutations rarely respond to the EGFR TKI therapy. Thus, combination therapy is essential for the treatment of lung cancers with KRAS mutations. EGFR TKI combined with inhibitors of MAPKs, PI3K/mTOR, HDAC, Wee1, PARP, CDK and Hsp90, even miRNAs and immunotherapy, were reviewed. Although the effects of the combination vary, the combined therapeutics are one of the best options at present to treat KRAS mutant lung cancer.

Smoking history and frequency of somatic KRAS mutations in adenocarcinoma of the lung

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7573-7573
Author(s):  
V. A. Miller ◽  
G. J. Riely ◽  
M. G. Kris ◽  
D. Rosenbaum ◽  
J. Marks ◽  
...  
Keyword(s):  
Cigarette Smoking ◽  
Mutational Analysis ◽  
Smoking History ◽  
Egfr Mutations ◽  
Molecular Testing ◽  
Kras Mutations ◽  
Exon 2 ◽  
Significant Difference ◽  
Never Smokers ◽  
Lung Adenocarcinomas

7573 Background: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are more common in patients with adenocarcinoma, especially those who smoked < 15 pack years (py). KRAS mutations are found in ∼25% of lung adenocarcinomas, most commonly in codons 12 and 13 of exon 2 (∼85%) and have been associated with poor prognosis in resected disease [Winton NEJM 2005] and resistance to EGFR tyrosine kinase inhibitors [Pao PLoS Med 2005]. KRAS mutations are uncommon in non-small cell lung cancer histologies other than adenocarcinoma. We sought to determine the association between quantitative measures of cigarette smoking and presence of KRAS mutations in lung adenocarcinomas. Methods: Standard direct sequencing techniques were used to identify KRAS codon 12 and 13 mutations in lung adenocarcinoma specimens from surgical resections between 2001 and 2006 and tumor specimens sent for KRAS molecular analysis in 2006. Surgical specimens were obtained from an institutional tumor bank. Detailed smoking history (age at first cigarette, packs per day, years smoked, years since quitting smoking) was obtained from the medical record and a patient-completed smoking questionnaire. Results: KRAS mutational analysis was performed on 408 lung adenocarcinomas from 242 women and 166 men. Median age was 68 (range 33–89). KRAS mutations were present in 19% (78/408, 95% CI 15 to 23%). The frequency of KRAS mutation was not associated with age or gender. The presence of KRAS mutations was not related to smoking history with 15% (9/61) of never smokers having KRAS mutations compared with 19% (51/275) of former smokers. When compared with never smokers, there was no significant difference in frequency of KRAS mutations for tumors from patients with 1–5 py (5%, p=0.44), 6- 10 py (12%, p=0.99), 11–15 py (25%, p=0.45), 16–25 py (16%, p=0.99), 26–50 py (25%, p=0.129), 51–75 py (20%, p=0.48), >75 py (20%, p=0.47) history of cigarette smoking. Conclusions: While the incidence of EGFR mutations has a strong inverse relationship with the amount of cigarettes smoked, allowing the selective molecular testing for EGFR mutations, the frequency of KRAS mutations cannot be predicted by age, gender, or smoking history. KRAS mutational analysis of all adenocarcinomas is required to reliably identify patients with KRAS mutations. No significant financial relationships to disclose.

Small cell lung cancer (SCLC) among patients who are never smokers.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7593-7593
Author(s):  
Anna M. Varghese ◽  
Helena Alexandra Yu ◽  
Helen H. Won ◽  
Camelia S. Sima ◽  
Gregory J. Riely ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Egfr Mutation ◽  
De Novo ◽  
Egfr Mutations ◽  
Kras Mutations ◽  
Lung Cancers ◽  
Never Smokers ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Generation Sequencing

7593 Background: Although most patients (pts) with SCLC are current or former smokers, SCLC has been reported in pts who are never smokers, most recently in pts with EGFR-mutant lung cancers who develop acquired resistance (AR) to EGFR tyrosine kinase inhibitors (TKIs). We describe clinical, pathologic, and molecular characteristics of never-smoking pts with SCLC at diagnosis and in the AR setting. Methods: We identified cases through systematic review of pts seen at MSKCC from 2005 – 2012. Smoking history was obtained prospectively. SCLC diagnosis was confirmed by expert pathology review. We collected age, sex, stage, treatment, and survival data. EGFR, KRAS, PIK3CA, and ALK testing and next generation sequencing of 279 cancer genes was performed on available samples. Results: 2.2% (23/1040, 95% CI 1.5 to 3.3%) of pts with SCLC seen at MSKCC were never smokers: 61% women, median 64 years, 74% extensive stage, and 22% with brain metastases at diagnosis. 83% (19/23) had de novo SCLC, whereas only 17% had SCLC as AR to EGFR TKI after treatment for EGFR-mutant lung cancers, all of whom had persistent EGFR mutation confirmed at resistance. Median survival from SCLC diagnosis is 23 months (95%CI: 11-26) for all pts and 23 months (95% CI: 8–27) for the 19 pts with de novo SCLC. Pathologic review demonstrated 19 cases of pure SCLC and 4 mixed histology cases with SCLC and other histologies. Treatment history was available for 15/19 pts with de novo SCLC: 53% etoposide-platinum sensitive. ALK rearrangement and KRAS mutations were identified in 0/5 and 0/10, respectively. One pt with de novo mixed SCLC and adenocarcinoma had an EGFR mutation and another pt with de novo pure SCLC had EGFR and PIK3CA mutations. Mutations were identified in p53 and Rb1 with amplification in TERT in 1 sample to date tested with next generation sequencing. Conclusions: 2% of pts with SCLC are never smokers. While transformation to SCLC can occur in the setting of AR to EGFR TKI, de novo SCLC occurs in the majority of our never smokers with this disease. EGFR mutations uniformly exist in SCLC in the AR setting. EGFR mutations were rare, and we found no KRAS mutations or ALK rearrangements. Comprehensive, multiplexed genotyping can aid in providing optimal care and facilitate research in this unique population.

Somatic mutation spectrum of non-small cell lung cancers (NSCLCs) from African Americans (AAs).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6038-6038
Author(s):  
Philip Edward Lammers ◽  
Velmalia Matthews-Smith ◽  
Ya-Lin Yun ◽  
Yumei Pan ◽  
Snjezana Zaja-Milatovic ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
North American Population ◽  
Molecular Testing ◽  
Chi Square ◽  
Kras Mutations ◽  
Lung Cancers ◽  
Anaplastic Lymphoma ◽  
Ffpe Tumor

6038 Background: In the AA population, previous studies have presented conflicting data on the frequency of EGFR mutations (Reinersman JTO 2011;Leidner JCO 2009), while frequencies of other gene mutations and translocations, including anaplastic lymphoma kinase (ALK), have not been described. Methods: 161 archival FFPE tumor specimens from self reported AA patients with any stage NSCLC from 1997-2010 were collected from 3 sites in Tennessee (132 samples) and one site in Michigan (29 samples). Samples were evaluated for known recurrent driver mutations in EGFR, KRAS, BRAF, NRAS, AKT1, PI3KCA, PTEN, HER-2, MEK1 by standard SNaPshot/sizing assays, and translocations in ALK by FISH. Clinical data was collected on 119 patients. Chi-square was used to compare the frequency of mutations in subgroups and Kaplan-Meier and log rank were used to calculate and compare PFS between groups. Results: 5.0% of tumors had EGFR mutations, 14.9% had KRAS mutations, 0.6% had a BRAF, AKT1, PI3KCA, or HER2 mutation, and 0% had NRAS, PTEN, or MEK1 mutations. Of 35 ‘pan-negative’ non-squamous specimens, 0 had ALK translocations. PFS was the same in those with and without KRAS mutation (p=0.74) and showed a trend towards improvement in those with EGFR mutation (p=0.08). The frequency of EGFR mutations was higher in samples from Detroit versus those from Tennessee (17% vs 2.3%, p<0.01), as was the frequency of adenocarcinoma (62% vs 44%, p<0.05). The frequency of EGFR mutations in never smokers was higher in the samples from Detroit versus Tennessee (83% vs 7.1%, p<0.01). Conclusions: In the largest tumor mutational profiling study of NSCLC from AAs to date, EGFR mutations occurred less frequently than would be expected from a North American population. We noted a regional difference, with fewer EGFR mutations in Tennessee than in Michigan, a finding that may have been the result of more adenocarcinoma samples from Michigan. The rates of other mutations and translocations including ALK were low. While lung cancer tumors should continue to undergo routine molecular testing to prioritize therapy, future comprehensive genotyping efforts should focus on identifying novel driver mutations in this population. Funding: 5RC1CA162260 R01CA060691 R01CA87895.

Long-term responders to PD-1 blockade in patients with advanced non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9549-9549
Author(s):  
Jia Luo ◽  
Chaitanya Bandlamudi ◽  
Biagio Ricciuti ◽  
Natalie Vokes ◽  
Adam Jacob Schoenfeld ◽  
...  
Keyword(s):  
Survival Curve ◽  
Initial Response ◽  
Egfr Mutations ◽  
Rank Test ◽  
Loss Of Function ◽  
Kras Mutations ◽  
Lung Cancers ◽  
Metastatic Lung ◽  
Term Response

9549 Background: Long-term response – the plateau of the survival curve – is the transcendent benefit from PD-1 blockade. However, only a subset of responses achieve substantial durability. The frequency, characteristics, and predictors of long-term responders (LTR) to PD-1 blockade are not well known and may differ from short-term responders (STR). Methods: Patients with advanced NSCLC treated with anti-PD-1/PD-L1 therapy from two institutions (MSK and DFCI) were examined. Responses were assessed by RECIST. LTR was defined as PR/CR lasting ≥ 24 months. STR was defined as PR/CR lasting < 12 months. Comparisons were also made to patients with progressive disease (PD). PD-L1 expression was assessed by IHC. TMB was assessed by targeted NGS; high TMB was defined as ≥ median of the cohort. A subset had detailed molecular profiling by MSK-IMPACT. Fisher’s exact and Mann-Whitney U tests were used to compare features, and the log-rank test was used to compare survival. Results: Of 2318 patients (MSK n = 1536, DFCI n = 782), 126 (5.4%, 95% CI 4.6-6.4%) achieved LTR, with similar rates in both cohorts. STR occurred in 139 (6%). Overall survival was longer in LTR compared to STR (median NR vs 19.6 months, HR 0.07, p < 0.001). LTR had deeper responses compared to STR (median best overall response -69% vs -46%, p < 0.001). Patients with LTR were younger ( < 65 years old) and had increased TMB (≥ median mut/Mb) compared to both STR and PD (p = 0.006, p = 0.03; p < 0.001, p < 0.001). The rate of LTR was enriched among patients with both high TMB/high PD-L1 compared to those with low TMB/low PD-L1 (9% vs 1%, OR 9.2, p < 0.001), while STR was similar in both groups (7% vs 6%). 2% of patients with sensitizing EGFR mutations (n = 243) achieved LTR. Loss of function variants in ARID1A (14% vs 2%), PTEN (8% vs 0%), and KEAP1 (12% vs 2%) were enriched in LTR compared to STR (p < 0.05 for each). Among patients with KRAS mutations, the rate of LTR was higher in those with co-mutation with TP53 compared to STK11 (11% vs 2%, p = 0.01). Conclusions: Long-term response (LTR, ongoing response ≥ 24 months) to PD-1 blockade is an uncommon but profound clinical outcome in metastatic lung cancers. Younger age and high TMB correlate with LTR; the combination of high TMB/high PD-L1 enriches for LTR but not STR. Features predicting long term response may be distinct from those predicting initial response.

scholarly journals Intertumoural Heterogeneity and Branch Evolution of Synchronous Multiple Primary Lung Adenocarcinomas by Next-Generation Sequencing Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Qinleng Zhang ◽  
Hui Jia ◽  
Zhendan Wang ◽  
Shaoyu Hao ◽  
Haiyan Huang ◽  
...  
Keyword(s):  
Egfr Mutations ◽  
Adenocarcinoma In Situ ◽  
Sequencing Analysis ◽  
Kras Mutations ◽  
Lung Cancers ◽  
Primary Lung Adenocarcinoma ◽  
Multiple Primary ◽  
Next Generation Sequencing Analysis ◽  
High Level ◽  
Lung Adenocarcinomas

ObjectivesMultiple primary lung cancers (MPLCs) are an increasingly well-known clinical phenomenon, but there is a lack of high-level evidence for their optimal clinical diagnosis and therapeutic approaches. Thus, we analysed genetic variation to determine the intertumoural heterogeneity and branch evolution of synchronous multiple primary lung adenocarcinomas.MethodsWe performed multiplex mutational sequencing on 93 synchronous multiple primary lung adenocarcinoma lesions from 42 patients who underwent surgical resection.ResultsThe high discordance rate of mutation was 92.9% (n=39) between tumours in individual patients. EGFR, TP53 and KRAS mutations were detected in 57 (61.3%), 19 (20.4%) and 11 (11.8%) of the 93 tumours, respectively. 16 cases of multiple primary lung adenocarcinomas simultaneously harboured EGFR mutations and TP53 mutations. Matching mutations between paired tumours were observed in 1 (2.4%) patient for P20. The genotypes were all EGFR L858R mutations, but the pathological type of P20T1 was lepidic predominant, and P20T2 was adenocarcinoma in situ. In the phylogenetic tree, genetic variations were divided into trunk, shared and branch subtypes. Branch mutations accounted for 91.09% of variations in sMPLA, while the ratio of trunk (4.95%) and shared (3.96%) variations was significantly lower.ConclusionsRemarkable intertumoural heterogeneity and frequent branch mutations were found in synchronous multiple primary lung adenocarcinomas.

Different EGFR/KRAS mutation spectrums in lung cancer between never smokers and heavy smokers.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10548-10548
Author(s):  
Kazuya Takamochi ◽  
Shiaki Oh ◽  
Kenji Suzuki
Keyword(s):  
Lung Cancer ◽  
Kras Mutation ◽  
Kinase Inhibitors ◽  
Smoking Status ◽  
Egfr Mutations ◽  
Blood Vessel Invasion ◽  
Kras Mutations ◽  
Lung Cancers ◽  
Never Smokers ◽  
Heavy Smokers

10548 Background: EGFR mutations are more commonly found in lung adenocarcinomas in never smokers, while KRAS mutations are more frequently present in those in heavy smokers. Although the incidence is low, EGFR mutations are also found in tumors in heavy smokers and KRAS mutations also occur in tumors in never smokers. Therefore, there may be different biological characteristics in EGFR/ KRAS mutated lung cancers according to the smoking status. Methods: This was a retrospective review of 382 patients with surgically resected lung cancers between February 2009 and March 2011. The clinicopathological factors (age, gender, histology, serum CEA level, pathological nodal status, lymphatic permeation, and blood vessel invasion) and EGFR/KRAS mutation spectrums were compared between never smokers (pack-year = 0, n = 161) and heavy smokers (pack-year > 20, n = 167). Results: EGFR mutations were detected in 88 (55%) never smokers and in 33 (20%) heavy smokers. In contrast, K-ras mutations were detected in 7 (4%) never smokers and in 31 (19%) heavy smokers. Both EGFR and KRAS mutations were more frequently observed in female never smokers and in male heavy smokers. The spectrum of both EGFR and KRAS mutation differed according to the smoking status. Minor EGFR mutations other than exon 21 L858R and exon 19 deletions that are activating mutations indicating the efficacy of EGFR tyrosine kinase inhibitors (TKIs) were more frequently found in heavy smokers than in never smokers. G→A transitions were more common KRAS mutations in never smokers and G→T transversions that are thought to be related to exposure to the polycyclic aromatic hydrocarbons found in cigarette smoke were more common KRAS mutations in heavy smokers. Conclusions: The EGFR/KRAS mutation spectrums in lung cancer were quite different in never smokers and heavy smokers. Further study is needed to evaluate the relationship between the efficacy of such molecular targeting agents as EGFR TKIs and the EGFR/KRAS mutation spectrums.

EGFR-KRAS genotyping and EGFR-CDX2 expression in sinonasal intestinal type adenocarcinomas: Toward a new targeted therapy?

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5565-5565
Author(s):  
Olivier Choussy ◽  
Olivia Abramovici ◽  
Alexandre Paviot ◽  
Aude Lamy ◽  
Daniele Dehesdin ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Intestinal Type ◽  
Egfr Mutations ◽  
Curative Surgery ◽  
Kras Mutations ◽  
Exon 2 ◽  
Efficient Treatment ◽  
Cdx2 Expression ◽  
Histological Phenotype ◽  
Genetic Profiles

5565 Background: Sinonasal carcinomas are very rare tumors which are sometimes not eligible for curative surgery. Alternative therapies (i.e. conventional chemotherapies/radiotherapy) are used but with poor results. Therefore, the need for a more efficient treatment is mandatory. Aims of our study: Comparing EGFR and KRAS genetic profiles, EGFR and CDX2 phenotypes of sinonasal intestinal type adenocarcinomas (ITAC) with colorectal adenocarcinomas (CRC). Methods: 41 patients were treated in our institution between 1983 and 2007. All pathological specimens were reclassified according to the 2005 WHO classification. An immunohistochemical (IHC) study was carried out for EGFR and CDX2 expression. We were able to analyze 38 of the 41 specimens for KRAS and EGFR mutations. SNaPshot multiplex system was used to determine the presence of the most common mutations which are located in exon 18, 20 and 21 for EGFR and in exon 2 (codon 12 and13) for KRAS. Fragment analysis method was used for EGFR exon 19 deletions. Results: Thirty five of the 38 patients were classified as ITAC (33 men and 2 women). The mean age was 64.5 years. Exposure to wood work was found in 29 cases (85%). CDX2 expression was present in 31 (89%) cases of ITAC and absent in all non intestinal adenocarcinomas (3 cases). EGFR was expressed in 29 ITACs (83%) with various degrees of IHC expression: 19 (56 %) 1+, 7 (21%) 2+, and 3 with 3+ immunopositivity. No EGFR mutation was found in the whole population; 5 ITAC patients (14%) disclosed KRAS mutations. Conclusions: Histological, phenotype and genetic profiles of ITAC are very similar to those of colorectal adenocarcinoma. These results suggest that ITACs with wt KRAS could respond to anti MoAb anti-EGFR therapy in the same way as metastatic CRC. We propose that all sinonasal tumors should undergo: firstly, CDX2 IHC in order to confirm the ITAC histological subtype and then KRAS genotyping to select the wt population which could benefit from such anti EGFR targeted therapy.

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