Summary Improvements in outcomes for patients with resectable lung cancers have plateaued. Clinical trials of resectable non-small-cell lung cancers with overall survival as the primary endpoint ...require a decade or longer to complete, are expensive, and limit innovation. A surrogate for survival, such as pathological response to neoadjuvant chemotherapy, has the potential to improve the efficiency of trials and expedite advances. 10% or less residual viable tumour after neoadjuvant chemotherapy, termed here major pathological response, meets criteria for a surrogate; major pathological response strongly associates with improved survival, is reflective of treatment effect, and captures the magnitude of the treatment benefit on survival. We support the incorporation of major pathological response as a surrogate endpoint for survival in future neoadjuvant trials of resectable lung cancers. Additional prospective studies are needed to confirm the validity and reproducibility of major pathological response within individual histological and molecular subgroups and with new drugs.
Osimertinib was initially approved for T790M-positive non-small cell lung cancer (NSCLC) and, more recently, for first-line treatment of
-mutant NSCLC. However, resistance mechanisms to osimertinib ...have been incompletely described.
Using cohorts from The University of Texas MD Anderson Lung Cancer Moonshot GEMINI and Moffitt Cancer Center lung cancer databases, we collected clinical data for patients treated with osimertinib. Molecular profiling analysis was performed at the time of progression in a subset of the patients.
In the 118 patients treated with osimertinib, 42 had molecular profiling at progression. T790M was preserved in 21 (50%) patients and lost in 21 (50%). EGFR C797 and L792 (26%) mutations were the most common resistance mechanism and were observed exclusively in T790M-preserved cases. MET amplification was the second most common alteration (14%). Recurrent alterations were observed in 22 genes/pathways, including PIK3CA, FGFR, and RET. Preclinical studies confirmed MET, PIK3CA, and epithelial-to-mesenchymal transition as potential resistance drivers. Alterations of cell-cycle genes were associated with shorter median progression-free survival (PFS, 4.4 vs. 8.8 months,
= 0.01). In 76 patients with progression, osimertinib was continued in 47 cases with a median second PFS (PFS2) of 12.6 months; 21 patients received local consolidation radiation with a median PFS of 15.5 months. Continuation of osimertinib beyond progression was associated with a longer overall survival compared with discontinuation (11.2 vs. 6.1 months,
= 0.02).
Osimertinib resistance is associated with diverse, predominantly EGFR-independent genomic alterations. Continuation of osimertinib after progression, alone or in conjunction with radiotherapy, may provide prolonged clinical benefit in selected patients.
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Money changes everything Goetzmann, William N
2016., 20170815, 2017, 2016, 2016-04-12, 2017-08-15
eBook
"A magnificent history of money and finance."--New York Times Book Review
"Convincingly makes the case that finance is a change-maker of change-makers."--Financial Times
In the aftermath of recent ...financial crises, it's easy to see finance as a wrecking ball: something that destroys fortunes and jobs, and undermines governments and banks. InMoney Changes Everything, leading financial historian William Goetzmann argues the exact opposite-that the development of finance has made the growth of civilizations possible. Goetzmann explains that finance is a time machine, a technology that allows us to move value forward and backward through time; and that this innovation has changed the very way we think about and plan for the future. He shows how finance was present at key moments in history: driving the invention of writing in ancient Mesopotamia, spurring the classical civilizations of Greece and Rome to become great empires, determining the rise and fall of dynasties in imperial China, and underwriting the trade expeditions that led Europeans to the New World. He also demonstrates how the apparatus we associate with a modern economy-stock markets, lines of credit, complex financial products, and international trade-were repeatedly developed, forgotten, and reinvented over the course of human history.
Exploring the critical role of finance over the millennia, and around the world, Goetzmann details how wondrous financial technologies and institutions-money, bonds, banks, corporations, and more-have helped urban centers to expand and cultures to flourish. And it's not done reshaping our lives, as Goetzmann considers the challenges we face in the future, such as how to use the power of finance to care for an aging and expanding population.
Money Changes Everythingpresents a fascinating look into the way that finance has steered the course of history.
Small-cell lung cancer (SCLC) is a disease with a poor prognosis and limited treatment options. Over the past 30 years, basic and clinical research have translated to little innovation in the ...treatment of this disease. The Study of Picoplatin Efficacy After Relapse (SPEAR) evaluated best supportive care with or without picoplatin for second-line SCLC treatment and failed to meet its primary end point of overall survival. As the largest second-line, randomized study in patients with SCLC, SPEAR provides an opportunity to critically examine the drug development model in this disease. In this Review, we discuss the current standard approach for the management of SCLC that progresses after first-line therapy, analyze the preliminary data that supported the evaluation of picoplatin in this setting, and critically evaluate the SPEAR trial design and results. Lastly, we present advances in the understanding of the molecular biology of SCLC that could potentially inform future clinical trials and hopefully lead to the successful development of molecular targeted agents for the treatment of this disease.
Preclinical data demonstrate a key role for the epidermal growth factor receptor (EGFR) in the carcinogenesis of cutaneous squamous cell carcinomas (CSCCs). There are, however, limited data on the ...efficacy of EGFR inhibitors in incurable, recurrent, and/or metastatic CSCC.
To determine the response rate to gefitinib in patients with CSCC not amenable to curative therapy including surgery or radiation.
This was a single-arm phase II study. A total of 40 patients were treated with gefitinib, 250 mg orally daily, until disease progression or intolerable toxicities. The prespecified target response rate of interest was 20%.
The overall response rate was 16% (95% confidence interval, 0.06-0.32; 6 partial responses in 37 evaluable patients). An additional 13 patients (35%) had stable disease at 8 weeks. The median durations of response and progression-free survival were 31.4 months (95% confidence interval, 3.91-not applicable) and 3.8 months (95% confidence interval, 2.2-5.7), respectively. The side effect profile was consistent with the previous experience with gefitinib in other tumor types.
This was a single-institution, single-arm study. The prespecified target response rate was not met.
Gefitinib demonstrated modest activity in incurable CSCC, with a favorable adverse event profile.
We previously demonstrated the association between epithelial-to-mesenchymal transition (EMT) and drug response in lung cancer using an EMT signature derived in cancer cell lines. Given the ...contribution of tumor microenvironments to EMT, we extended our investigation of EMT to patient tumors from 11 cancer types to develop a pan-cancer EMT signature.
Using the pan-cancer EMT signature, we conducted an integrated, global analysis of genomic and proteomic profiles associated with EMT across 1,934 tumors including breast, lung, colon, ovarian, and bladder cancers. Differences in outcome and in vitro drug response corresponding to expression of the pan-cancer EMT signature were also investigated.
Compared with the lung cancer EMT signature, the patient-derived, pan-cancer EMT signature encompasses a set of core EMT genes that correlate even more strongly with known EMT markers across diverse tumor types and identifies differences in drug sensitivity and global molecular alterations at the DNA, RNA, and protein levels. Among those changes associated with EMT, pathway analysis revealed a strong correlation between EMT and immune activation. Further supervised analysis demonstrated high expression of immune checkpoints and other druggable immune targets, such as PD1, PD-L1, CTLA4, OX40L, and PD-L2, in tumors with the most mesenchymal EMT scores. Elevated PD-L1 protein expression in mesenchymal tumors was confirmed by IHC in an independent lung cancer cohort.
This new signature provides a novel, patient-based, histology-independent tool for the investigation of EMT and offers insights into potential novel therapeutic targets for mesenchymal tumors, independent of cancer type, including immune checkpoints.
An aneuploid-immune paradox encompasses somatic copy-number alterations (SCNAs), unleashing a cytotoxic response in experimental precancer systems, while conversely being associated with immune ...suppression and cytotoxic-cell depletion in human tumors, especially head and neck cancer (HNSC). We present evidence from patient samples and cell lines that alterations in chromosome dosage contribute to an immune hot-to-cold switch during human papillomavirus-negative (HPV
) head and neck tumorigenesis. Overall SCNA (aneuploidy) level was associated with increased CD3
and CD8
T cell microenvironments in precancer (mostly CD3
, linked to trisomy and aneuploidy), but with T cell-deficient tumors. Early lesions with 9p21.3 loss were associated with depletion of cytotoxic T cell infiltration in
mutant tumors; and with aneuploidy were associated with increased NK-cell infiltration. The strongest driver of cytotoxic T cell and Immune Score depletion in oral cancer was 9p-arm level loss, promoting profound decreases of pivotal IFN-γ-related chemokines (e.g., CXCL9) and pathway genes. Chromosome 9p21.3 deletion contributed mainly to cell-intrinsic senescence suppression, but deletion of the entire arm was necessary to diminish levels of cytokine, JAK-STAT, and Hallmark NF-κB pathways. Finally, 9p arm-level loss and
-
codeletion (at 9p24) were predictive markers of poor survival in recurrent HPV
HNSC after anti-PD-1 therapy; likely amplified by independent aneuploidy-induced immune-cold microenvironments observed here. We hypothesize that 9p21.3 arm-loss expansion and epistatic interactions allow oral precancer cells to acquire properties to overcome a proimmunogenic aneuploid checkpoint, transform and invade. These findings enable distinct HNSC interception and precision-therapeutic approaches, concepts that may apply to other CN-driven neoplastic, immune or aneuploid diseases, and immunotherapies.
Reirradiation of head and neck (H&N) cancer is a clinical challenge. Proton radiation therapy (PRT) offers dosimetric advantages for normal tissue sparing and may benefit previously irradiated ...patients. Here, we report our initial experience with the use of PRT for H&N reirradiation, with focus on clinical outcomes and toxicity.
We retrospectively reviewed the records of patients who received H&N reirradiation with PRT from April 2011 through June 2015. Patients reirradiated with palliative intent or without prior documentation of H&N radiation therapy were excluded. Radiation-related toxicities were recorded according to the Common Terminology Criteria for Adverse Events Version 4.0.
The conditions of 60 patients were evaluated, with a median follow-up time of 13.6 months. Fifteen patients (25%) received passive scatter proton therapy (PSPT), and 45 (75%) received intensity modulated proton therapy (IMPT). Thirty-five patients (58%) received upfront surgery, and 44 (73%) received concurrent chemotherapy. The 1-year rates of locoregional failure-free survival, overall survival, progression-free survival, and distant metastasis-free survival were 68.4%, 83.8%, 60.1%, and 74.9%, respectively. Eighteen patients (30%) experienced acute grade 3 (G3) toxicity, and 13 (22%) required a feeding tube at the end of PRT. The 1-year rates of late G3 toxicity and feeding tube independence were 16.7% and 2.0%, respectively. Three patients may have died of reirradiation-related effects (1 acute and 2 late).
Proton beam therapy can be a safe and effective curative reirradiation strategy, with acceptable rates of toxicity and durable disease control.
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