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1.
Curr Oncol ; 30(11): 9611-9626, 2023 Oct 31.
Article in English | MEDLINE | ID: mdl-37999116

ABSTRACT

Pancreatic cancer is a devastating disease with a poor prognosis. Novel chemotherapeutics in pancreatic cancer have shown limited success, illustrating the urgent need for new treatments. Lurbinectedin (PM01183; LY-01017) received FDA approval in 2020 for metastatic small cell lung cancer on or after platinum-based chemotherapy and is currently undergoing clinical trials in a variety of tumor types. Lurbinectedin stalls and degrades RNA Polymerase II and introduces breaks in DNA, causing subsequent apoptosis. We now demonstrate lurbinectedin's highly efficient killing of human-derived pancreatic tumor cell lines PANC-1, BxPC-3, and HPAF-II as a single agent. We further demonstrate that a combination of lurbinectedin and irinotecan, a topoisomerase I inhibitor with FDA approval for advanced pancreatic cancer, results in the synergistic killing of pancreatic tumor cells. Western blot analysis of combination therapy indicates an upregulation of γH2AX, a DNA damage marker, and the Chk1/ATR pathway, which is involved in replicative stress and DNA damage response. We further demonstrate that the triple combination between lurbinectedin, irinotecan, and 5-fluorouracil (5-FU) results in a highly efficient killing of tumor cells. Our results are developing insights regarding molecular mechanisms underlying the therapeutic efficacy of a novel combination drug treatment for pancreatic cancer.


Subject(s)
Fluorouracil , Pancreatic Neoplasms , Humans , Irinotecan/pharmacology , Irinotecan/therapeutic use , Fluorouracil/pharmacology , Fluorouracil/therapeutic use , Carbolines/pharmacology , Carbolines/therapeutic use , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms
3.
Clin Lung Cancer ; 24(4): 329-338, 2023 06.
Article in English | MEDLINE | ID: mdl-36842852

ABSTRACT

BACKGROUND: This study evaluated the association between elevated C-reactive protein (CRP) and clinical outcomes among adults treated with surgery for non-small cell lung cancer (NSCLC) in the US. MATERIALS AND METHODS: Adults with NSCLC who underwent lung cancer surgery and had ≥1 CRP measurement prior to, or >1 month following, index surgery were identified in the Optum Clinformatics claims database. The association between elevated CRP (>10 mg/L) and risk of NSCLC recurrence/death was assessed separately during the 6 months before surgery (pre surgery cohort) and 2 years following surgery (post-surgery cohort) using multivariate regressions and Kaplan-Meier analysis. RESULTS: After adjusting for baseline demographic and clinical characteristics among patients in the pre surgery cohort with index surgery between 2016 to 2020 (n = 104), the incidence rate ratio (IRR) for NSCLC recurrence between elevated vs. non-elevated CRP was 2.17 (95% confidence interval [CI]=1.03-4.60; P = .04). In the post surgery cohort (n = 264), the adjusted IRR for disease recurrence (elevated vs. non-elevated CRP) was 2.22 (95% CI=1.05-4.70; P = .04). In the pre surgery cohort, the odds of death were nearly two-fold (odds ratio [OR]=1.91; 95% CI=1.06-3.42; P = .03) among patients with elevated CRP. In the post surgery cohort, the OR was 1.62 (95% CI=0.88-2.97; P = .12). Among those with persistently elevated CRP prior to surgery, there was a significant overall trend of increased CRP over the 5-year period. CONCLUSION: These results support the association between elevated CRP and a higher risk of NSCLC recurrence/death in pre- and postsurgery cohorts. This study may shed lights on inflammation-suppressing treatments in patients with NSCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Adult , Humans , Carcinoma, Non-Small-Cell Lung/surgery , Prognosis , C-Reactive Protein/analysis , C-Reactive Protein/metabolism , Lung Neoplasms/surgery , Retrospective Studies , Neoplasm Recurrence, Local
4.
Adv Radiat Oncol ; 8(2): 101130, 2023.
Article in English | MEDLINE | ID: mdl-36845618

ABSTRACT

Purpose: In patients with locally advanced, unresectable non-small cell lung cancer (NSCLC), the standard of care is concurrent chemoradiation (CRT) followed by consolidative immunotherapy with durvalumab. Pneumonitis is a known adverse event of both radiation therapy and immune checkpoint inhibitors such as durvalumab. We sought to characterize pneumonitis rates and dosimetric predictors of pneumonitis in a real-world population of patients with NSCLC treated with definitive CRT followed by consolidative durvalumab. Methods and Materials: Patients with NSCLC from a single institution who were treated with definitive CRT followed by consolidative durvalumab were identified. Outcomes of interest included pneumonitis incidence, type of pneumonitis, progression-free survival, and overall survival. Results: Sixty-two patients were included in our data set treated from 2018 to 2021 with a median follow-up of 17 months. The rate of grade 2+ pneumonitis in our cohort was 32.3%, and the rate of grade 3+ pneumonitis was 9.7%. Lung dosimetry parameters including V20 ≥30% and mean lung dose (MLD) >18 Gy were found to be correlated with increased rates of grade 2+ and grade 3+ pneumonitis. Patients with a lung V20 ≥30% had a grade 2+ pneumonitis rate at 1 year of 49.8% compared with 17.8% in patients with a lung V20 <30% (P = .015). Similarly, patients with an MLD >18 Gy had a grade 2+ pneumonitis rate at 1 year of 52.4% compared with 25.8% in patients with an MLD ≤18 Gy (P = .01). Moreover, heart dosimetry parameters including mean heart dose ≥10 Gy were found to be correlated with increased rates of grade 2+ pneumonitis. The estimated 1-year overall survival and progression-free survival of our cohort were 86.8% and 64.1%, respectively. Conclusions: The modern management of locally advanced, unresectable NSCLC involves definitive chemoradiation followed by consolidative durvalumab. Pneumonitis rates were higher than expected in this cohort, particularly for patients with a lung V20 ≥30%, MLD >18 Gy, and mean heart dose ≥10 Gy, suggesting that more stringent radiation planning dose constraints may be needed.

5.
EBioMedicine ; 82: 104127, 2022 Aug.
Article in English | MEDLINE | ID: mdl-35810561

ABSTRACT

BACKGROUND: Pre-treatment FDG-PET/CT scans were analyzed with machine learning to predict progression of lung malignancies and overall survival (OS). METHODS: A retrospective review across three institutions identified patients with a pre-procedure FDG-PET/CT and an associated malignancy diagnosis. Lesions were manually and automatically segmented, and convolutional neural networks (CNNs) were trained using FDG-PET/CT inputs to predict malignancy progression. Performance was evaluated using area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. Image features were extracted from CNNs and by radiomics feature extraction, and random survival forests (RSF) were constructed to predict OS. Concordance index (C-index) and integrated brier score (IBS) were used to evaluate OS prediction. FINDINGS: 1168 nodules (n=965 patients) were identified. 792 nodules had progression and 376 were progression-free. The most common malignancies were adenocarcinoma (n=740) and squamous cell carcinoma (n=179). For progression risk, the PET+CT ensemble model with manual segmentation (accuracy=0.790, AUC=0.876) performed similarly to the CT only (accuracy=0.723, AUC=0.888) and better compared to the PET only (accuracy=0.664, AUC=0.669) models. For OS prediction with deep learning features, the PET+CT+clinical RSF ensemble model (C-index=0.737) performed similarly to the CT only (C-index=0.730) and better than the PET only (C-index=0.595), and clinical only (C-index=0.595) models. RSF models constructed with radiomics features had comparable performance to those with CNN features. INTERPRETATION: CNNs trained using pre-treatment FDG-PET/CT and extracted performed well in predicting lung malignancy progression and OS. OS prediction performance with CNN features was comparable to a radiomics approach. The prognostic models could inform treatment options and improve patient care. FUNDING: NIH NHLBI training grant (5T35HL094308-12, John Sollee).


Subject(s)
Lung Neoplasms , Positron Emission Tomography Computed Tomography , Fluorodeoxyglucose F18 , Humans , Lung Neoplasms/diagnostic imaging , Lung Neoplasms/therapy , Machine Learning , Positron Emission Tomography Computed Tomography/methods , Positron-Emission Tomography
6.
Am J Cancer Res ; 12(2): 729-743, 2022.
Article in English | MEDLINE | ID: mdl-35261798

ABSTRACT

The American Cancer Society estimates that ~15% of all lung cancers are categorized as small cell lung cancer (SCLC) with an overall five-year survival rate of less than 7%. Due to disease aggressiveness, more other malignancies, the standard of care is based on clinical efficacy rather than helpful biomarkers. Lurbinectedin is a small molecule RNA polymerase II inhibitor that binds the minor groove of DNA to induce double-strand breaks. Lurbinectedin has efficacy towards SCLC cells at sub-nM concentration and received accelerated FDA approval in 2020 for metastatic SCLC that progressed on platinum-based therapy. ONC201/TIC10 is a TRAIL pathway-inducing compound that with demonstrated clinical efficacy in H3K27M-mutated diffuse midline glioma and neuroendocrine tumors, in early phase clinical trials. We hypothesized that combining ONC201 and lurbinectedin may yield synergistic and targeted killing of SCLC cells. SCLC cell lines H1048, H1105, H1882, and H1417 were treated with ONC201 and lurbinectedin and cell viability was determined using a CellTiter-Glo assay using varying drug concentrations. Synergistic growth inhibition of SCLC cells was noted with combination of ONC201 and lurbinectedin. Induction of the integrated stress response mediator ATF4 and CHOP was observed with ONC201 and lurbinectedin along with induction of PARP cleavage indicative of apoptosis in response to cellular stress. Additionally, SCLC lines treated with the combination therapy displayed increased DNA breakage-related proteins such as phosphorylated Chk-1, Wee1 and γ-H2AX. Combination index revealed the most potent synergy occurred at the concentrations of 0.16 µM ONC201 and 0.05 nM lurbinectedin in the H1048 cell line, demonstrating highly efficient and selective killing of these tumor cells in vitro. While these therapies showed potency against the cell lines derived from SCLC patients, it is noteworthy that the combination showed significantly less toxicity to healthy human lung epithelial cells. Future studies could explore the combination of ONC201 and lurbinectedin in SCLC cell lines, SCLC patient-derived organoids, other tumor types, including in vivo studies and clinical translation.

7.
Front Pharmacol ; 12: 747180, 2021.
Article in English | MEDLINE | ID: mdl-34531756

ABSTRACT

Lung cancer is the second most common cancer in the United States, and small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. In SCLC, more than other malignancies, the standard of care is based on clinical demonstration of efficacy, and less on a mechanistic understanding of why certain treatments work better than others. This is in large part due to the virulence of the disease, and lack of clinically or biologically relevant biomarkers beyond routine histopathology. While first line therapies work in the majority of patients with extensive stage disease, development of resistance is nearly universal. Although neuroendocrine features, Rb and p53 mutations are common, the current lack of actionable biomarkers has made it difficult to develop more effective treatments. Some progress has been made with the application of immune checkpoint inhibitors. There are new agents, such as lurbinectedin, that have completed late-phase clinical testing while other agents are still in the pre-clinical phase. ONC201/TIC10 is an imipridone with strong in vivo and in vitro antitumor properties and activity against neuroendocrine tumors in phase 1 clinical testing. ONC201 activates the cellular integrated stress response and induces the TRAIL pro-apoptotic pathway. Combination treatment of lurbinectedin with ONC201 are currently being investigated in preclinical studies that may facilitate translation into clinical trials for SCLC patients.

8.
Ann Diagn Pathol ; 54: 151799, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34311302

ABSTRACT

Lung adenocarcinoma is currently staged based on invasive tumor size, excluding areas of lepidic (in situ) growth. Invasive tumor size may be determined by pathologic assessment of a surgical specimen or radiographic assessment on computerized tomography (CT) scan. When invasive tumor size is the primary stage determinate, radiographic-pathologic discordance or discordant interpretation among pathologists may alter tumor stage and treatment. We reviewed 40 cases of non-mucinous pulmonary adenocarcinoma in which tumor size was the only stage-determinant. We determined the inter-observer variability when microscopically assessing architectural patterns and its effect on pathologic stage and treatment. Additionally, we correlated pathologic and radiographic assessment of invasive tumor size and its effect on tumor stage and treatment. The intraclass correlation among three pathologists was 0.9879; all three pathologists agreed on T-stage in 75% of cases. Four cases of pathologic disagreement had the potential to alter therapy. Intraclass correlation between the pathologists and invasive tumor size determined by CT scan was 0.8482. In 23 cases (57.5%) the pathologic T-stage differed (it increased >90% of the time) from clinical T-stage (determined by CT scan) based on invasive tumor size. Five of the radiographically-pathologically discrepant cases resulted in a stage change that had the potential to alter adjuvant therapy. Our findings suggest the stage differences in pathologic staging are prognostically relevant, but unlikely to impact routine selection of adjuvant therapy, and the observed variability in clinical stage tends to select against overuse of neoadjuvant therapy when invasive tumor size is the primary stage-determinant.


Subject(s)
Adenocarcinoma of Lung/pathology , Adenocarcinoma/pathology , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Adenocarcinoma/diagnosis , Adenocarcinoma/therapy , Adenocarcinoma of Lung/diagnosis , Adenocarcinoma of Lung/therapy , Aged , Female , Humans , Lung/pathology , Lung Neoplasms/diagnosis , Male , Middle Aged , Neoplasm Staging/methods , Observer Variation , Prognosis , Retrospective Studies
9.
JCO Precis Oncol ; 5: 325-332, 2021 01.
Article in English | MEDLINE | ID: mdl-34151132

ABSTRACT

For patients with surgically resected disease, multiple studies suggest a benefit of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in delaying cancer recurrence. The necessary duration of therapy for benefit is unknown. MATERIALS AND METHODS: This randomized phase II study enrolled patients with completely resected stage IA-IIIB EGFR-mutant non-small-cell lung cancer (American Joint Committee on Cancer 7th edition) after stage-appropriate standard-of-care adjuvant therapy. Patients were randomly assigned 1:1 to 3 months or 2 years of adjuvant afatinib starting at 30 mg by mouth daily. Computed tomography imaging was performed every 6 months for 3 years and then annually. The primary study end point for this planned 92-patient trial was recurrence rate at 2 years from randomization. A 20% improvement (from 70% with 3 months to 90% with 2 years) was targeted. RESULTS: Forty-six patients enrolled and 45 were treated. The assigned course of afatinib treatment was completed by 96% (22/23) of patients in the 3-month group and only 41% (9/22) in the 2-year group. The 2-year recurrence-free survival (RFS) rates were 70% in the 3-month group and 81% in the 2-year group (P = .55). The median RFS was 42.8 months in the 3-month group and 58.6 months in the 2-year group. Side effects were consistent with those previously described for afatinib. CONCLUSION: Recurrences at 2 years were 11% less common with 2 years versus 3 months of adjuvant afatinib. This difference did not meet the 20% primary study target, likely because of underaccrual and early drug discontinuation on the 2-year group. With the availability of osimertinib with better efficacy and tolerability than earlier-generation agents, the optimal duration of adjuvant EGFR TKI therapy remains an important question.


Subject(s)
Afatinib/therapeutic use , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/surgery , Chemotherapy, Adjuvant , ErbB Receptors/genetics , Female , Humans , Lung Neoplasms/pathology , Lung Neoplasms/surgery , Male , Middle Aged , Neoplasm Staging , Prospective Studies , Time Factors
10.
Nat Rev Clin Oncol ; 18(9): 547-557, 2021 09.
Article in English | MEDLINE | ID: mdl-33911215

ABSTRACT

The treatment goal for patients with early-stage lung cancer is cure. Multidisciplinary discussions of surgical resectability and medical operability determine the modality of definitive local treatment (surgery or radiotherapy) and the associated systemic therapies to further improve the likelihood of cure. Trial evidence supports cisplatin-based adjuvant therapy either after surgical resection or concurrently with radiotherapy. Consensus guidelines support neoadjuvant chemotherapy in lieu of adjuvant chemotherapy and carboplatin-based regimens for patients who are ineligible for cisplatin. The incorporation of newer agents, now standard for patients with stage IV lung cancer, into the curative therapy paradigm has lagged owing to inefficient trial designs, the lengthy follow-up needed to assess survival end points and a developmental focus on the advanced-stage disease setting. Surrogate end points, such as pathological response, are being studied and might shorten trial durations. In 2018, the anti-PD-L1 antibody durvalumab was approved for patients with stage III lung cancer after concurrent chemoradiotherapy. Since then, the study of targeted therapies and immunotherapies in patients with early-stage lung cancer has rapidly expanded. In this Review, we present the current considerations in the treatment of patients with early-stage lung cancer and explore the current and future state of clinical research to develop systemic therapies for non-metastatic lung cancer.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Therapies, Investigational/trends , Carcinoma, Non-Small-Cell Lung/pathology , Chemotherapy, Adjuvant , Combined Modality Therapy , Humans , Lung Neoplasms/pathology , Neoadjuvant Therapy , Neoplasm Staging , Therapies, Investigational/methods
11.
Eur J Cancer ; 145: 234-244, 2021 03.
Article in English | MEDLINE | ID: mdl-33431285

ABSTRACT

BACKGROUND: How corticosteroid use affects treatment response to chemotherapy and immune-checkpoint inhibitors (CICPIs) remains unknown. We assessed how systemic corticosteroid exposure before CICPI modifies the effect of CICPI on outcomes among patients with metastatic non-small cell lung cancer (mNSCLC) or extensive-stage small-cell lung cancer (ES-SCLC). METHODS: We conducted a retrospective cohort study using electronic health records to examine patients with mNSCLC or ES-SCLC who received chemotherapy (CT) between 1st April 2015 and 31st January 2018 or CICPI between 1st February 2018 and 31st August 2019. We excluded those with an actionable driver mutation. Baseline corticosteroid use was defined as systemic corticosteroids within 28 days before the initiation of CT or CICPI, not including premedications. Coprimary outcomes included overall survival (OS), real-world progression (rwP), and real-world progression-free survival (rwPFS) in CICPI-treated corticosteroid users versus non-users. We used inverse probability of treatment weighting (IPW) to adjust for potential confounding. RESULTS: The cohort of 316 patients (median [interquartile range] age, 67 [61-73] years; 156 [49%] male) included 228 CT-treated and 88 CICPI-treated patients. After applying IPW, characteristics were well-balanced between the CT and CICPI groups, and steroid users and non-users. Using CT-treated steroid non-users as a common comparator, CICPI-treated steroid users were as likely as CICPI-treated steroid non-users to die (users IPW hazard ratio [HR] = 0.67, 95% CI = 0.35-1.28 versus non-users IPW-HR = 0.88, 95% C = I0.55-1.42; p = 0.49), have rwP (IPW-HR = 0.35, 95% C = I0.12-0.99 versus IPW-HR = 0.41, 95% C = I0.24-0.70; p = 0.77), or experience rwPFS (IPW-HR = 0.56, 95% C = I0.29-1.09 versus IPW-HR = 0.69, 95% CI0.46-1.03; p = 0.59). CONCLUSION: Corticosteroid use before CICPIs was not associated with worse outcomes, suggesting that corticosteroids should be used with CICPIs when indicated.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/drug therapy , Small Cell Lung Carcinoma/drug therapy , Adrenal Cortex Hormones/adverse effects , Aged , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Non-Small-Cell Lung/secondary , Disease Progression , Electronic Health Records , Female , Humans , Immune Checkpoint Inhibitors/adverse effects , Lung Neoplasms/immunology , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Progression-Free Survival , Retrospective Studies , Small Cell Lung Carcinoma/immunology , Small Cell Lung Carcinoma/pathology , Time Factors
13.
Histopathology ; 78(6): 896-904, 2021 May.
Article in English | MEDLINE | ID: mdl-33231320

ABSTRACT

AIMS: Nuclear protein in testis (NUT) carcinoma, an aggressive tumour driven by NUTM1 rearrangements, often involves the lung/mediastinum and shows squamous differentiation. We encountered an index patient with a thoracic NUT carcinoma diagnosed by molecular testing, showing extensive pleural involvement and diffuse thyroid transcription factor-1 (TTF-1) expression, initially suggestive of lung adenocarcinoma with pseudomesotheliomatous growth. We thus gathered an institutional series of thoracic NUT carcinomas to examine their pathological spectrum. METHODS AND RESULTS: We searched for thoracic NUT carcinomas in our surgical pathology files and in 2289 consecutive patients with primary thoracic tumours investigated with RNA-based assays. We performed NUT immunohistochemistry on 425 additional lung adenocarcinomas. Collectively, we identified six patients (five men and one woman; age 31-80 years; four never-smokers) with thoracic NUT carcinomas confirmed by molecular testing (including five with positive NUT immunohistochemistry). They died at 2.3-12.9 months (median, 2.8 months) after presentation. Two patients were diagnosed by histopathological assessment, and the remaining four (including the index patient) were diagnosed by molecular testing. Analysis of the index case revealed expression of multiple neuroendocrine markers and TTF-1; no ultrastructural evidence of neuroendocrine differentiation was noted. No additional NUT-positive cases were found by immunohistochemical screening. CONCLUSIONS: Although NUT carcinoma classically shows squamous differentiation, it can rarely express TTF-1 (even diffusely) and/or multiple neuroendocrine markers. This immunophenotypic spectrum may lead to diagnostic confusion with pulmonary adenocarcinoma, neuroendocrine tumour, and others. To circumvent this pitfall, NUT immunohistochemistry and/or NUTM1 molecular testing should be considered in primitive-appearing tumours, regardless of their immunophenotypic features.


Subject(s)
Carcinoma/pathology , Lung Neoplasms/pathology , Neoplasm Proteins/metabolism , Nuclear Proteins/metabolism , Thyroid Nuclear Factor 1/metabolism , Adult , Aged , Aged, 80 and over , Carcinoma/metabolism , Female , Humans , Lung Neoplasms/metabolism , Male , Middle Aged
14.
Oncologist ; 25(11): e1691-e1700, 2020 11.
Article in English | MEDLINE | ID: mdl-32820577

ABSTRACT

BACKGROUND: Metastatic esophagogastric cancers (EGCs) have a poor prognosis with an approximately 5% 5-year survival. Additional treatment approaches are needed. c-MET gene-amplified tumors are an uncommon but potentially targetable subset of EGC. Clinical characteristics and outcomes were evaluated in patients with MET-amplified EGC and compared with those without MET amplification to facilitate identification of these patients and possible treatment approaches. PATIENTS AND METHODS: Patients with locally advanced or metastatic MET-amplified EGC at Massachusetts General Hospital (MGH) were identified using fluorescent in situ hybridization analysis, with a gene-to-control ratio of ≥2.2 defined as positive. Non-MET-amplified patients identified during the same time period who had undergone tumor genotyping and treatment at MGH were evaluated as a comparison group. RESULTS: We identified 233 patients evaluated for MET amplification from 2002 to 2019. MET amplification was seen in 28 (12%) patients versus 205 (88%) patients without amplification. Most MET-amplified tumors occurred in either the distal esophagus (n = 9; 32%) or gastroesophageal junction (n = 10; 36%). Of MET-amplified patients, 16 (57%) had a TP53 mutation, 5(18%) had HER2 co-amplification, 2 (7.0%) had EGFR co-amplification, and 1 (3.5%) had FGFR2 co-amplification. MET-amplified tumors more frequently had poorly differentiated histology (19/28, 68.0% vs. 66/205, 32%; p = .02). Progression-free survival to initial treatment was substantially shorter for all MET-amplified patients (5.6 vs. 8.8 months, p = .026) and for those with metastatic disease at presentation (4.0 vs. 7.6 months, p = .01). Overall, patients with MET amplification had shorter overall survival (19.3 vs. 24.6 months, p = .049). No difference in survival was seen between low MET-amplified tumors (≥2.2 and <25 MET copy number) compared with highly amplified tumors (≥25 MET copy number). CONCLUSION: MET-amplified EGC represents a distinct clinical entity characterized by rapid progression and short survival. Ideally, the identification of these patients will provide opportunities to participate in clinical trials in an attempt to improve outcomes. IMPLICATIONS FOR PRACTICE: This article describes 233 patients who received MET amplification testing and reports (a) a positivity rate of 12%, similar to the rate of HER2 positivity in this data set; (b) the clinical characteristics of poorly differentiated tumors and nodal metastases; and (c) markedly shorter progression-free survival and overall survival in MET-amplified tumors. Favorable outcomes are reported for patients treated with MET inhibitors. Given the lack of published data in MET-amplified esophagogastric cancers and the urgent clinical importance of identifying patients with MET amplification for MET-directed therapy, this large series is a valuable addition to the literature and will have an impact on future practice.


Subject(s)
Esophageal Neoplasms , Gene Amplification , Stomach Neoplasms , Adult , Aged , Esophageal Neoplasms/genetics , Esophageal Neoplasms/therapy , Esophagogastric Junction , Female , Humans , In Situ Hybridization, Fluorescence , Male , Massachusetts , Middle Aged , Prognosis , Proto-Oncogene Proteins c-met , Stomach Neoplasms/genetics , Stomach Neoplasms/therapy , Treatment Outcome
15.
R I Med J (2013) ; 103(3): 28-32, 2020 Apr 01.
Article in English | MEDLINE | ID: mdl-32236158

ABSTRACT

The diagnosis and treatment of lung cancer is entering a new era. With increasingly advanced diagnostic tools, we are more able than ever to pinpoint genetic changes in tumor cells that allow us to treat with highly effective, targeted therapy. In a growing number of patients, we are able to avoid cytotoxic therapies altogether. The recent advent of immunotherapy has led to a similar paradigm shift. This article will review the latest advances in tumor tissue and blood biomarkers directly as they relate to available treatments. Specifically, we will review activating and sensitizing gene mutations, gene fusions, PD-L1 tumor score, and close with an appraisal of the rapidly advancing field of peripheral blood biomarkers.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Molecular Targeted Therapy , Precision Medicine/trends , Antineoplastic Agents/pharmacology , Biomarkers, Tumor/analysis , Carcinoma, Non-Small-Cell Lung/genetics , Cell Cycle Checkpoints , ErbB Receptors/genetics , Humans , Immunotherapy , Lung Neoplasms/genetics , Mutation , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/genetics , Survival Rate
16.
Clin Cancer Res ; 26(11): 2535-2545, 2020 06 01.
Article in English | MEDLINE | ID: mdl-32086345

ABSTRACT

PURPOSE: Most ALK-positive lung cancers will develop ALK-independent resistance after treatment with next-generation ALK inhibitors. MET amplification has been described in patients progressing on ALK inhibitors, but frequency of this event has not been comprehensively assessed. EXPERIMENTAL DESIGN: We performed FISH and/or next-generation sequencing on 207 posttreatment tissue (n = 101) or plasma (n = 106) specimens from patients with ALK-positive lung cancer to detect MET genetic alterations. We evaluated ALK inhibitor sensitivity in cell lines with MET alterations and assessed antitumor activity of ALK/MET blockade in ALK-positive cell lines and 2 patients with MET-driven resistance. RESULTS: MET amplification was detected in 15% of tumor biopsies from patients relapsing on next-generation ALK inhibitors, including 12% and 22% of biopsies from patients progressing on second-generation inhibitors or lorlatinib, respectively. Patients treated with a second-generation ALK inhibitor in the first-line setting were more likely to develop MET amplification than those who had received next-generation ALK inhibitors after crizotinib (P = 0.019). Two tumor specimens harbored an identical ST7-MET rearrangement, one of which had concurrent MET amplification. Expressing ST7-MET in the sensitive H3122 ALK-positive cell line induced resistance to ALK inhibitors that was reversed with dual ALK/MET inhibition. MET inhibition resensitized a patient-derived cell line harboring both ST7-MET and MET amplification to ALK inhibitors. Two patients with ALK-positive lung cancer and acquired MET alterations achieved rapid responses to ALK/MET combination therapy. CONCLUSIONS: Treatment with next-generation ALK inhibitors, particularly in the first-line setting, may lead to MET-driven resistance. Patients with acquired MET alterations may derive clinical benefit from therapies that target both ALK and MET.


Subject(s)
Anaplastic Lymphoma Kinase/metabolism , Carcinoma, Non-Small-Cell Lung/genetics , Drug Resistance, Neoplasm/genetics , Gene Amplification , Lung Neoplasms/genetics , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/genetics , Aminopyridines , Anaplastic Lymphoma Kinase/genetics , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Crizotinib/pharmacology , Gene Expression Regulation, Neoplastic , High-Throughput Nucleotide Sequencing , Humans , Lactams , Lactams, Macrocyclic/pharmacology , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Prognosis , Pyrazoles , Tumor Cells, Cultured
19.
Cancer ; 125(13): 2213-2221, 2019 07 01.
Article in English | MEDLINE | ID: mdl-30913304

ABSTRACT

BACKGROUND: Antiangiogenic therapy is a proven therapeutic modality for refractory gastric and gastroesophageal junction adenocarcinoma. This trial assessed whether the addition of a high affinity angiogenesis inhibitor, ziv-aflibercept, could improve the efficacy of first-line mFOLFOX6 (oxaliplatin, leucovorin, and bolus plus infusional 5- fluorouracil) in metastatic esophagogastric adenocarcinoma. METHODS: Patients with treatment-naive metastatic esophagogastric adenocarcinoma were randomly assigned (in a 2:1 ratio) in a multicenter, placebo-controlled, double-blind trial to receive first-line mFOLFOX6 with or without ziv-aflibercept (4 mg/kg) every 2 weeks. The primary endpoint was 6-month progression-free survival (PFS). RESULTS: Sixty-four patients were randomized to receive mFOLFOX6 and ziv-aflibercept (43 patients) or mFOLFOX6 and a placebo (21 patients). There was no difference in the PFS, overall survival, or response rate. Patients treated with mFOLFOX6/ziv-aflibercept tended to be more likely to discontinue study treatment for reasons other than progressive disease (P = .06). The relative dose intensity of oxaliplatin and 5-fluorouracil was lower in the mFOLFOX6/ziv-aflibercept arm during the first 12 and 24 weeks of the trial. There were 2 treatment-related deaths due to cerebral hemorrhage and bowel perforation in the mFOLFOX6/ziv-aflibercept cohort. CONCLUSIONS: Ziv-aflibercept did not increase the anti-tumor activity of first-line mFOLFOX6 in metastatic esophagogastric cancer, potentially because of decreased dose intensity of FOLFOX. Further evaluation of ziv-aflibercept in unselected, chemotherapy-naive patients with metastatic esophagogastric adenocarcinoma is not warranted.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Esophageal Neoplasms/drug therapy , Esophagogastric Junction/drug effects , Stomach Neoplasms/drug therapy , Adenocarcinoma/secondary , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Double-Blind Method , Esophageal Neoplasms/pathology , Esophagogastric Junction/pathology , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Leucovorin/administration & dosage , Lymphatic Metastasis , Male , Middle Aged , Organoplatinum Compounds/administration & dosage , Prognosis , Stomach Neoplasms/pathology , Survival Rate
20.
J Clin Oncol ; 37(2): 97-104, 2019 01 10.
Article in English | MEDLINE | ID: mdl-30444685

ABSTRACT

PURPOSE: Given the pivotal role of epidermal growth factor receptor (EGFR) inhibitors in advanced EGFR-mutant non-small-cell lung cancer (NSCLC), we tested adjuvant erlotinib in patients with EGFR-mutant early-stage NSCLC. MATERIALS AND METHODS: In this open-label phase II trial, patients with resected stage IA to IIIA (7th edition of the American Joint Committee on Cancer staging system) EGFR-mutant NSCLC were treated with erlotinib 150 mg per day for 2 years after standard adjuvant chemotherapy with or without radiotherapy. The study was designed for 100 patients and powered to demonstrate a primary end point of 2-year disease-free survival (DFS) greater than 85%, improving on historic data of 76%. RESULTS: Patients (N = 100) were enrolled at seven sites from January 2008 to May 2012; 13% had stage IA disease, 32% had stage IB disease, 11% had stage IIA disease, 16% had stage IIB disease, and 28% had stage IIIA disease. Toxicities were typical of erlotinib; there were no grade 4 or 5 adverse events. Forty percent of patients required erlotinib dose reduction to 100 mg per day and 16% to 50 mg per day. The intended 2-year course was achieved in 69% of patients. The median follow-up was 5.2 years, and 2-year DFS was 88% (96% stage I, 78% stage II, 91% stage III). Median DFS and overall survival have not been reached; 5-year DFS was 56% (95% CI, 45% to 66%), 5-year overall survival was 86% (95% CI, 77% to 92%). Disease recurred in 40 patients, with only four recurrences during erlotinib treatment. The median time to recurrence was 25 months after stopping erlotinib. Of patients with recurrence who underwent rebiopsy (n = 24; 60%), only one had T790M mutation detected. The majority of patients with recurrence were retreated with erlotinib (n = 26; 65%) for a median duration of 13 months. CONCLUSION: Patients with EGFR-mutant NSCLC treated with adjuvant erlotinib had an improved 2-year DFS compared with historic genotype-matched controls. Recurrences were rare for patients receiving adjuvant erlotinib, and patients rechallenged with erlotinib after recurrence experienced durable benefit.


Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Erlotinib Hydrochloride/therapeutic use , Lung Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/enzymology , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Chemotherapy, Adjuvant , Disease-Free Survival , ErbB Receptors/genetics , Female , Humans , Lung Neoplasms/enzymology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Male , Middle Aged , Mutation , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/enzymology , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Protein Kinase Inhibitors/therapeutic use
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