Investigating the genomic alteration improved the clinical outcome of aged patients with lung carcinoma

Abstract Background Lung carcinoma is a common geriatric disease. The development of genotype-targeted therapies greatly improved the management of lung carcinoma. However, the treatment for old patients can be more complex than that for young individuals. Results To investigate the benefits of genetic detection for older patients with lung carcinoma, we explored the genomic profiling of 258 patients with more than 55 years using a targeted next generation sequencing, and some of these patients were treated with targeted therapies based on the results of genomic detection. KRAS codon 61 mutations were found in 15.2% KRAS-mutated patients, which tend to be co-existing with other classical activating mutations other than codons 12/13. Acquired EGFR C797S mutations were identified in 2 cases and ERBB2 amplification was identified in 1 case. All these 3 cases developed resistance to EGFR tyrosine kinase inhibitors and showed expected results of their followed therapies. The median progression-free survival and median overall survival of patients treated with molecular targeted therapies were better than those of patients treated with chemoradiotherapy alone. Conclusions Our findings revealed the specific genomic profiles of patients older than 55 years with lung carcinoma and suggested that these old patients have been benefit from the genetic detection, which helped identify druggable mutations and distinguish resistance mechanisms.

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Updates on the CDK4/6 Inhibitory Strategy and Combinations in Breast Cancer

Cells ◽

10.3390/cells8040321 ◽

2019 ◽

Vol 8 (4) ◽

pp. 321 ◽

Cited By ~ 25

Author(s):

Sobhani ◽

D’Angelo ◽

Pittacolo ◽

Roviello ◽

Miccoli ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Targeted Therapies ◽

Randomized Clinical Trials ◽

Kinase Inhibitors ◽

Growth Factor Receptor ◽

Predictive Biomarkers ◽

Progression Free Survival ◽

Her2 Positive ◽

Retinoblastoma Tumor

Breast Cancer (BC) is the second most common type of cancer worldwide and displays the highest cancer-related mortality among women worldwide. Targeted therapies have revolutionized the way BC has been treated in recent decades, improving the life expectancies of millions of women. Among the different molecular pathways that have been of interest for the development of targeted therapies are the Cyclin-Dependent Kinases (CDK). CDK inhibitors are a class of molecules that already exist in nature and those belonging to the Cyclin dependent kinase inhibitors family INK4 that specifically inhibit CDK4/6 proteins. CDK4/6 inhibitors specifically block the transition from the G1 to the S phase of the cell cycle by dephosphorylation of the retinoblastoma tumor suppressor protein. In the past four years, the CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, received their first FDA approval for the treatment of Hormone Receptor (HR)-positive and Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer after showing significant improvements in progression-free survival in the PALOMA-1, MONALEESA-2 and the MONARCH-2 randomized clinical trials, respectively. After the encouraging results from these clinical trials, CDK4/6 inhibitors have also been investigated in other BC subtypes. In HER2-positive BC, a combination of CDK4/6 inhibitors with HER2-targeted therapies showed promise in preclinical studies and their clinical evaluation is ongoing. Moreover, in triple-negative BC, the efficacy of CDK4/6 inhibitors has been investigated in combination with other targeted therapies or immunotherapies. This review summarizes the molecular background and clinical efficacy of CDK4/6 inhibitors as single agents or in combination with other targeted therapies for the treatment of BC. Future directions for ongoing clinical trials and predictive biomarkers will be further debated.

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Predictors of Response to Targeted Therapies for Gastrointestinal Stromal Tumors

Archives of Pathology & Laboratory Medicine ◽

10.5858/arpa.2011-0082-ra ◽

2012 ◽

Vol 136 (5) ◽

pp. 483-489 ◽

Cited By ~ 26

Author(s):

Andrea Marrari ◽

Andrew J. Wagner ◽

Jason L. Hornick

Keyword(s):

Imatinib Mesylate ◽

Targeted Therapies ◽

Gastrointestinal Stromal Tumors ◽

Kinase Inhibitors ◽

Clinical Decision Making ◽

Progression Free Survival ◽

Clinical Decision ◽

Myelogenous Leukemia ◽

Stromal Tumors ◽

Mutational Status

Context.—The inhibition of oncogenic kinase signaling is a successful strategy to treat both hematologic and solid malignancies. Patients with chronic myelogenous leukemia, lung adenocarcinoma, renal cell carcinoma, and gastrointestinal stromal tumors are experiencing tremendous clinical benefits from targeted therapies in the form of kinase inhibitors. These drugs marked a revolution in cancer treatment, not only for their safety and efficacy, but also because they continue to expand our knowledge of the pathophysiology of cancer. Objective.—To provide a summary of the biologic predictors of gastrointestinal stromal tumor behavior and response to targeted therapies that currently help guide clinical decision making. Data Sources.—Published articles pertaining to the diagnosis, molecular genetics, prognostication, clinical behavior, and treatment of gastrointestinal stromal tumors, as well as experiences in a multidisciplinary sarcoma clinic. Conclusions.—In gastrointestinal stromal tumors, the strongest predictor of response to targeted therapies is the mutational status of KIT or PDGFRA. Patients whose tumors harbor a KIT exon 11 mutation benefit the most from imatinib mesylate therapy, in terms of response rate, progression-free survival, and overall survival. Conversely, tumors without detectable mutations in either gene (“wild-type” gastrointestinal stromal tumors) are generally not responsive to imatinib mesylate.

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Efficacy and acquired resistance for EGFR-TKI plus thoracic SBRT in patients with advanced EGFR-mutant non–small-cell lung cancer: a propensity-matched retrospective study

BMC Cancer ◽

10.1186/s12885-021-08228-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xia Wang ◽

Zhimin Zeng ◽

Jing Cai ◽

Peng Xu ◽

Pingan Liang ◽

...

Keyword(s):

Retrospective Study ◽

Kinase Inhibitors ◽

Acquired Resistance ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Resistance Mechanisms ◽

Egfr Mutations ◽

Control Group ◽

Real World Data ◽

Baseline Characteristics

Abstract Background This retrospective study aimed to evaluate the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with stereotactic body radiation therapy (SBRT) and to elucidate potential mechanisms of acquired resistance. Methods Patients with advanced NSCLC harboring positive EGFR mutations after initial TKI therapy for at least 8 weeks were eligible for SBRT between August 2016 and August 2019. Eligible patients were treated with thoracic SBRT, and TKI was continued after SBRT until it was considered ineffective. The control group was treated with TKIs monotherapy. Propensity score matching (PSM, ratio of 1:2) was used to account for differences in baseline characteristics. Overall survival (OS), progression-free survival (PFS), treatment safety and resistance mechanisms were evaluated. Results Three hundred eight patients were included in the study population. Among them, 262 patients received TKIs alone, and 46 patients received TKIs with SBRT. Baseline characteristics were not significantly different between the two cohorts after PSM. The median PFS was 19.4 months in the TKIs +SBRT group compared to 13.7 months in the TKIs group (p = 0.034). An influence on OS has not yet been shown (p = 0.557). Of the 135 patients evaluated after PSM, 28 and 71 patients in the TKIs and TKIs +SBRT cohorts, respectively, had plasma cell-free DNA (cfDNA) next-generation sequencing (NGS) performed at baseline and disease progression. In the TKIs +SBRT cohort, the NGS results showed that T790M mutations were detected in 64.3% (18/28) of patients. Patients in the TKIs cohort exhibited fewer T790M-positive mutations (40.8%, p = 0.035) compared to patients in the TKIs +SBRT cohort. Conclusion Real world data prove that TKIs plus thoracic SBRT significantly extend PFS with tolerable toxicity. The mutation ratio of T790M was increased in the TKIs +SBRT group compared to the TKIs only group. Further randomized studies are warranted.

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Novel resistance mechanisms to first-generation EGFR tyrosine kinase inhibitors: A perspective study in NSCLC patients using targeted next generation sequencing.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e20576 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e20576-e20576

Author(s):

Ying Jin ◽

Jianjun Zhang ◽

Ming Chen ◽

Yang Shao ◽

Xun Shi ◽

...

Keyword(s):

First Generation ◽

Kinase Inhibitors ◽

Acquired Resistance ◽

Resistance Mechanisms ◽

Egfr Mutations ◽

T790m Mutation ◽

Targeted Next Generation Sequencing ◽

Egfr Tyrosine Kinase Inhibitors ◽

Nsclc Patients ◽

Egfr T790m

e20576 Background:Patients with non-small-cell lung cancer (NSCLC) harboring sensitive epithelial growth factor receptor (EGFR) mutations invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Identification of actionable mutations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. Currently, the known mechanisms of acquired resistance includes: the secondary gatekeeper EGFR-T790M mutation, activation of members of downstream signaling pathways such as PI3K/AKT/mTOR pathway, activation of bypass signaling such as MET, and changes in tumor histology. However, the mechanisms in the remaining patients are still unknown. Methods:In this prospective study, thirty-one advanced NSCLC patients initially carrying sensitive EGFR mutations and subsequently developing acquired resistance to the first-generation EGFR-TKIs were enrolled. Pre-treatment tumor samples as well as re-biopsies of tumor and plasma when the patients were diagnosed with EGFR-TKI resistance were acquired, followed by mutation profiling using targeted next generation sequencing (NGS) on 416 cancer-related genes. Results: In total, 55% of patients were identified to carry acquired secondary EGFR-T790M mutation. Three patients (~10%) harbor EGFR-T854A mutation, which has been reported as another TKI resistant mutation. 26% and 19% of cases accumulated TP53 and RB1 mutations, respectively. In T790M/T854A-negative cases, 30% of patients acquired MET amplification. Other potential acquired resistance mechanisms includes single nucleotide variants (SNVs) in genes such as SMAD4, DNMT3A, GNAS, ATM, KRAS, PIK3CA and TET2, and copy number variations (CNVs) in genes such as CDK4, MDM2, MYC, RICTOR and ERBB2. Conclusions:The study depicted the genetic landscapes comprehensively in matched pre- and post-EGFR-TKIs samples of NSCLC population resistant to first generation TKI treatments. Our analysis demonstrates new perspectives for further study of resistance and putting forward corresponding relevant tactics against the challenge of disease progression. Clinical trial information: NCT02804217.

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Detection of TP53 Mutations in Tissue or Liquid Rebiopsies at Progression Identifies ALK+ Lung Cancer Patients with Poor Survival

Cancers ◽

10.3390/cancers11010124 ◽

2019 ◽

Vol 11 (1) ◽

pp. 124 ◽

Cited By ~ 9

Author(s):

Petros Christopoulos ◽

Steffen Dietz ◽

Martina Kirchner ◽

Anna-Lena Volckmar ◽

Volker Endris ◽

...

Keyword(s):

Lung Cancer ◽

Kinase Inhibitors ◽

Stage Iv ◽

Progression Free Survival ◽

Resistance Mechanisms ◽

Wild Type ◽

Tp53 Mutations ◽

Lung Cancer Patients ◽

Anaplastic Lymphoma ◽

Nsclc Patients

Anaplastic lymphoma kinase (ALK) sequencing can identify resistance mechanisms and guide next-line therapy in ALK+ non-small-cell lung cancer (NSCLC), but the clinical significance of other rebiopsy findings remains unclear. We analysed all stage-IV ALK+ NSCLC patients with longitudinally assessable TP53 status treated in our institutions (n = 62). Patients with TP53 mutations at baseline (TP53mutbas, n = 23) had worse overall survival (OS) than patients with initially wild-type tumours (TP53wtbas, n = 39, 44 vs. 62 months in median, p = 0.018). Within the generally favourable TP53wtbas group, detection of TP53 mutations at progression defined a “converted” subgroup (TP53mutconv, n = 9) with inferior OS, similar to that of TP53mutbas and shorter than that of patients remaining TP53 wild-type (TP53wtprogr, 45 vs. 94 months, p = 0.043). Progression-free survival (PFS) under treatment with tyrosine kinase inhibitors (TKI) for TP53mutconv was comparable to that of TP53mutbas and also shorter than that of TP53wtprogr cases (5 and 8 vs. 13 months, p = 0.0039). Fewer TP53wtprogr than TP53mutbas or TP53mutconv cases presented with metastatic disease at diagnosis (67% vs. 91% or 100%, p < 0.05). Thus, acquisition of TP53 mutations at progression is associated with more aggressive disease, shorter TKI responses and inferior OS in ALK+ NSCLC, comparable to primary TP53 mutated cases.

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Real-world implementation of sequential targeted therapies for EGFR-mutated lung cancer

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835921996509 ◽

2021 ◽

Vol 13 ◽

pp. 175883592199650

Author(s):

Nikolaus Magios ◽

Farastuk Bozorgmehr ◽

Anna-Lena Volckmar ◽

Daniel Kazdal ◽

Martina Kirchner ◽

...

Keyword(s):

Lung Cancer ◽

Targeted Therapies ◽

Kinase Inhibitors ◽

Growth Factor Receptor ◽

Resistance Mechanisms ◽

Subsequent Treatment ◽

Clinical Deterioration ◽

Published Data ◽

Tki Treatment ◽

Nsclc Patients

Background: Epidermal growth factor receptor-mutated (EGFR+) non-small-cell lung cancer (NSCLC) patients failing tyrosine kinase inhibitors (TKI) can benefit from next-line targeted therapies, but implementation is challenging. Methods: EGFR+ NSCLC patients treated with first/second-generation (1G/2G) TKI at our institution with a last follow-up after osimertinib approval (February 2016), were analyzed retrospectively, and the results compared with published data under osimertinib. Results: A total of 207 patients received erlotinib (37%), gefitinib (16%) or afatinib (47%). The median age was 66 years, with a predominance of female (70%), never/light-smokers (69%). T790M testing was performed in 174/202 progressive cases (86%), positive in 93/174 (53%), and followed by osimertinib in 87/93 (94%). Among the 135 deceased patients, 94 (70%) received subsequent systemic treatment (43% chemotherapy, 39% osimertinib), while 30% died without, either before (4%) or after progression, due to rapid clinical deterioration (22%), patient refusal of further therapy (2%), or severe competing illness (2%). Lack of subsequent treatment was significantly (4.5x, p < 0.001) associated with lack of T790M testing, whose most frequent cause (in approximately 50% of cases) was also rapid clinical decline. Among the 127 consecutive patients with failure of 1G/2G TKI started after November 2015, 47 (37%) received osimertinib, with a median overall survival of 36 months versus 24 and 21 months for patients with alternative and no subsequent therapies ( p = 0.003). Conclusion: Osimertinib after 1G/2G TKI failure prolongs survival, but approximately 15% and 30% of patients forego molecular retesting and subsequent treatment, respectively, mainly due to rapid clinical deterioration. This is an important remediable obstacle to sequential TKI treatment for EGFR+ NSCLC. It pertains also to other actionable resistance mechanisms emerging under 1G/2G inhibitors or osimertinib, whose rate for lack of next-line therapy is similar (approximately 35% in the FLAURA/AURA3 trials), and highlights the need for closer monitoring alongside broader profiling of TKI-treated EGFR+ NSCLC in the future.

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MicroRNAs as Predictive Biomarkers of Resistance to Targeted Therapies in Gastrointestinal Tumors

Biomedicines ◽

10.3390/biomedicines9030318 ◽

2021 ◽

Vol 9 (3) ◽

pp. 318

Author(s):

Valentina Angerilli ◽

Francesca Galuppini ◽

Gianluca Businello ◽

Luca Dal Santo ◽

Edoardo Savarino ◽

...

Keyword(s):

Drug Resistance ◽

Targeted Therapies ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Acquired Resistance ◽

Predictive Biomarkers ◽

Resistance Mechanisms ◽

Specific Gene ◽

Primary Resistance ◽

Ideal Candidate

The advent of precision therapies against specific gene alterations characterizing different neoplasms is revolutionizing the oncology field, opening novel treatment scenarios. However, the onset of resistance mechanisms put in place by the tumor is increasingly emerging, making the use of these drugs ineffective over time. Therefore, the search for indicators that can monitor the development of resistance mechanisms and above all ways to overcome it, is increasingly important. In this scenario, microRNAs are ideal candidate biomarkers, being crucial post-transcriptional regulators of gene expression with a well-known role in mediating mechanisms of drug resistance. Moreover, as microRNAs are stable molecules, easily detectable in tissues and biofluids, they are the ideal candidate biomarker to identify patients with primary resistance to a specific targeted therapy and those who have developed acquired resistance. The aim of this review is to summarize the major studies that have investigated the role of microRNAs as mediators of resistance to targeted therapies currently in use in gastro-intestinal neoplasms, namely anti-EGFR, anti-HER2 and anti-VEGF antibodies, small-molecule tyrosine kinase inhibitors and immune checkpoint inhibitors. For every microRNA and microRNA signature analyzed, the putative mechanisms underlying drug resistance were outlined and the potential to be translated in clinical practice was evaluated.

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Liquid Biopsy: A New Tool for Overcoming CDKi Resistance Mechanisms in Luminal Metastatic Breast Cancer

10.20944/preprints202104.0667.v1 ◽

2021 ◽

Author(s):

Miriam González-Conde ◽

Celso Yanez ◽

Rafael López-López ◽

Clotilde Costa

Keyword(s):

Breast Cancer ◽

Liquid Biopsy ◽

Hormone Receptors ◽

Kinase Inhibitors ◽

Combined Therapy ◽

Endocrine Resistance ◽

Metastatic Breast ◽

Progression Free Survival ◽

Relevant Information ◽

Resistance Mechanisms

Breast cancer (BC) is the most common cancer diagnosed in women worldwide. Approximately 70% of BC patients have the luminal subtype, which expresses hormone receptors (HR+). Adjuvant endocrine treatments are the standard of care for HR+/HER2- BC patients. Over time, approximately 30% of those patients develop endocrine resistance and metastatic disease. Cyclin-dependent kinase inhibitors (CDKi) in combination with an aromatase inhibitor or fulvestrant have demonstrated superior efficacies in increasing progression-free survival, with a safe toxicity profile, in HR+/HER2- metastatic BC patients. CDKi blocks kinases 4/6, preventing G1/S cell cycle transition. However, not all patients respond to CDKi, and those who do respond ultimately develop resistance to the combined therapy. Studies in tumour tissues and cell lines have tried to elucidate the mechanisms underlying this progression, but there are still no conclusive data. Over the last few years, liquid biopsy has contributed relevant information. Circulating tumour materials are potential prognostic markers for determining patient prognosis in metastatic luminal BC, for monitoring disease and for treatment selection. This review outlines the different studies performed using liquid biopsy in patients with HR+ metastatic BC treated with CDKi plus endocrine therapy. We focus mainly on those studies that describe possible resistance mechanisms in circulating tumour-derived material.

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Comparison of Resistance Spectra after First and Second Line Osimertinib Treatment Detected by Liquid Biopsy

Cancers ◽

10.3390/cancers13122861 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2861

Author(s):

Balázs Jóri ◽

Stefanie Schatz ◽

Len Kaller ◽

Bettina Kah ◽

Julia Roeper ◽

...

Keyword(s):

Liquid Biopsy ◽

Second Generation ◽

Kinase Inhibitors ◽

Progression Free Survival ◽

Resistance Mechanisms ◽

Added Value ◽

Third Generation ◽

Second Line ◽

Pik3ca Mutations ◽

First And Second Generation

Since 2009, several first, second, and third generation EGFR tyrosine kinase inhibitors (TKI) have been approved for targeted treatment of EGFR mutated metastatic non-small lung cancer (NSCLC). A vast majority of patients is improving quickly on treatment; however, resistance is inevitable and typically occurs after one year for TKI of the first and second generation. Osimertinib, a third generation TKI, has recently been approved for first line treatment in the palliative setting and is expected to become approved for the adjuvant setting as well. Progression-free survival (PFS) under osimertinib is superior to its predecessors but its spectrum of resistance alterations appears significantly more diverse compared to first and second generation EGFR TKI. As resistance mechanisms to osimertinib are therapeutically targetable in some cases, it is important to comprehensively test for molecular alterations in the relapse scenario. Liquid biopsy may be advantageous over tissue analysis as it has the potential to represent tumor heterogeneity and clonal diversification. We have previously shown high concordance of hybrid capture (HC) based next generation sequencing (NGS) in liquid biopsy versus solid tumor biopsies. In this study, we now present real-word data from 56 patients with metastatic NSCLC that were tested by liquid biopsy at the time of disease progression on mostly second line treated osimertinib treatment. We present examples of single and multiple TKI resistance mechanisms, including mutations in multiple pathways, copy number changes and rare fusions of RET, ALK, FGFR3 and BRAF. In addition, we present the added value of HC based NGS to reveal polyclonal resistance development at the DNA level encoding multiple EGFR C797S and PIK3CA mutations.

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Liquid Biopsy: A New Tool for Overcoming CDKi Resistance Mechanisms in Luminal Metastatic Breast Cancer

Journal of Personalized Medicine ◽

10.3390/jpm11050407 ◽

2021 ◽

Vol 11 (5) ◽

pp. 407

Author(s):

Miriam González-Conde ◽

Celso Yañez-Gómez ◽

Rafael López-López ◽

Clotilde Costa

Keyword(s):

Breast Cancer ◽

Liquid Biopsy ◽

Hormone Receptors ◽

Kinase Inhibitors ◽

Combined Therapy ◽

Endocrine Resistance ◽

Metastatic Breast ◽

Progression Free Survival ◽

Relevant Information ◽

Resistance Mechanisms

Breast cancer (BC) is the most common cancer diagnosed in women worldwide. Approximately 70% of BC patients have the luminal subtype, which expresses hormone receptors (HR+). Adjuvant endocrine treatments are the standard of care for HR+/HER2− BC patients. Over time, approximately 30% of those patients develop endocrine resistance and metastatic disease. Cyclin-dependent kinase inhibitors (CDKi), in combination with an aromatase inhibitor or fulvestrant, have demonstrated superior efficacies in increasing progression-free survival, with a safe toxicity profile, in HR+/HER2− metastatic BC patients. CDKi blocks kinases 4/6, preventing G1/S cell cycle transition. However, not all of the patients respond to CDKi, and those who do respond ultimately develop resistance to the combined therapy. Studies in tumour tissues and cell lines have tried to elucidate the mechanisms that underlie this progression, but there are still no conclusive data. Over the last few years, liquid biopsy has contributed relevant information. Circulating tumour materials are potential prognostic markers for determining patient prognosis in metastatic luminal BC, for monitoring disease, and for treatment selection. This review outlines the different studies performed using liquid biopsy in patients with HR+ metastatic BC treated with CDKi plus endocrine therapy. We mainly focus on those studies that describe the possible resistance mechanisms in circulating tumour-derived material.

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