EGFR-mutated NSCLC is a genetically heterogeneous disease that includes more than 200 distinct mutations. The implications of mutational subtype for both prognostic and predictive value are being ...increasingly understood. Although the most common EGFR mutations—exon 19 deletions or L858R mutations—predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs), it is now being recognized that outcomes may be improved in patients with exon 19 deletions. Additionally, 10% of patients will have an uncommon EGFR mutation, and response to EGFR TKI therapy is highly variable depending on the mutation. Given the growing recognition of the genetic and clinical variation seen in this disease, the development of comprehensive bioinformatics-driven tools to both analyze response in uncommon mutation subtypes and inform clinical decision making will be increasingly important. Clinical trials of novel EGFR TKIs should prospectively account for the presence of uncommon mutation subtypes in study design.
Anti-PD-1 therapy yields objective clinical responses in 30-40% of advanced melanoma patients. Since most patients do not respond, predictive biomarkers to guide treatment selection are needed. We ...hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 therapy response. In this study, across 60 melanoma cell lines, we find bimodal expression patterns of MHC-II, while MHC-I expression was ubiquitous. A unique subset of melanomas are capable of expressing MHC-II under basal or IFNγ-stimulated conditions. Using pathway analysis, we show that MHC-II(+) cell lines demonstrate signatures of 'PD-1 signalling', 'allograft rejection' and 'T-cell receptor signalling', among others. In two independent cohorts of anti-PD-1-treated melanoma patients, MHC-II positivity on tumour cells is associated with therapeutic response, progression-free and overall survival, as well as CD4(+) and CD8(+) tumour infiltrate. MHC-II(+) tumours can be identified by melanoma-specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection.
Standard first-line treatment of advanced urothelial cell carcinoma involves cisplatin-based chemotherapy, with carboplatin or immune checkpoint inhibitor therapy (ICI) reserved for ...cisplatin-ineligible individuals.
Using a large de-identified electronic health record-derived database of patients with advanced urothelial cell carcinoma in the USA, we examined trends in utilization of first-line systemic therapies in cisplatin-eligible patients from 1 January 2015 to 31 March 2018.
Among 1181 cisplatin-eligible patients, the quarterly proportion who received first-line ICI increased from 1 to 42% (p
<0.001), while the proportion who received cisplatin-based chemotherapy decreased from 53 to 33% (p
= 0.018). Patients receiving ICI were older than those receiving cisplatin (median age: 75 vs 68).
Our analysis suggests rising off-label ICI use in cisplatin-eligible individuals, potentially because of ICI's favorable toxicity profile.
Natural language processing (NLP) offers significantly faster variable extraction compared to traditional human extraction but cannot interpret complicated notes as well as humans can. Thus, we ...hypothesized that an "NLP-assisted" extraction system, which uses humans for complicated notes and NLP for uncomplicated notes, could produce faster extraction without compromising accuracy.
The aim of this study was to develop and pilot an NLP-assisted extraction system to leverage the strengths of both human and NLP extraction of prostate cancer Gleason scores.
We collected all available clinical and pathology notes for prostate cancer patients in an unselected academic biobank cohort. We developed an NLP system to extract prostate cancer Gleason scores from both clinical and pathology notes. Next, we designed and implemented the NLP-assisted extraction system algorithm to categorize notes into "uncomplicated" and "complicated" notes. Uncomplicated notes were assigned to NLP extraction and complicated notes were assigned to human extraction. We randomly reviewed 200 patients to assess the accuracy and speed of our NLP-assisted extraction system and compared it to NLP extraction alone and human extraction alone.
Of the 2051 patients in our cohort, the NLP system extracted a prostate surgery Gleason score from 1147 (55.92%) patients and a prostate biopsy Gleason score from 1624 (79.18%) patients. Our NLP-assisted extraction system had an overall accuracy rate of 98.7%, which was similar to the accuracy of human extraction alone (97.5%; P=.17) and significantly higher than the accuracy of NLP extraction alone (95.3%; P<.001). Moreover, our NLP-assisted extraction system reduced the workload of human extractors by approximately 95%, resulting in an average extraction time of 12.7 seconds per patient (vs 256.1 seconds per patient for human extraction alone).
We demonstrated that an NLP-assisted extraction system was able to achieve much faster Gleason score extraction compared to traditional human extraction without sacrificing accuracy.
Lung cancer is the leading cause of cancer-related death worldwide. For decades, cytotoxic chemotherapy has been the mainstay of treatment for the majority of patients, yet median survival remains ...poor and side effects from chemotherapy are not trivial. Immune checkpoint inhibitors, which exert antitumor effects by inhibiting negative T-cell regulators, are changing the landscape of treatment options for patients with non-small-cell lung cancer (NSCLC). The anti-PD-1 antibodies nivolumab and pembrolizumab are approved by the US FDA for treatment of patients with NSCLC and other tumor types. Additional agents are in clinical development. This review provides an update on the PD-1 and PD-L1 immune checkpoint inhibitors currently being evaluated in NSCLC patients.
Early palliative care (PC) improves quality of life and prolongs survival for patients with metastatic non-small cell lung cancer (NSCLC). Despite these benefits, patient- and provider-specific ...barriers lead to underutilization of PC. To investigate these barriers, this 2 part study surveyed United States oncologists and patients with NSCLC.
Oncologists in the International Association for the Study of Lung Cancer membership directory were surveyed on referral practice and attitudes regarding the role of PC for patients with NSCLC. Patients with advanced NSCLC at the Vanderbilt Ingram Cancer Center were surveyed separately regarding their understanding of PC and factors influencing them to seek referral.
Of 279 oncologists, 93 responded. Eighty-three percent believe definitive evidence exists supporting early PC; however, in practice, oncologists only refer an average of 19% of patients at diagnosis. Reasons for not referring included lack of symptoms (56%), belief that oncologists can manage PC independently (46%), not wanting to burden patients with appointments (41%), concern that referral may not be well received (38%), and long wait times (20%). Of 100 patients with NSCLC, 64% were unfamiliar with PC. Six percent had seen a PC provider. Ninety-eight percent of patients would accept referral if recommended by their oncologist. Patients desired referral for uncontrolled pain (95%), weak support system (86%), other cancer-related symptoms (85%), goals of care discussion (76%), and depression/anxiety (76%).
Although most oncologists acknowledge benefits of early PC for patients with metastatic NSCLC, a minority of patients are referred. Few patients with NSCLC are familiar with PC, but most are interested in referral.
Early palliative care implementation has been shown to be beneficial for patients with metastatic non–small-cell lung cancer. This study surveyed United States oncologists and patients with metastatic non–small-cell lung cancer on their practices and attitudes regarding the role of early palliative care referral. Our study highlights that few patients are referred at the time of diagnosis, likely owing to several noteworthy barriers.
Limited data compare first-line carboplatin-based chemotherapy and immune checkpoint blockade in cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients. The primary evidence guiding ...treatment decisions was a recent Food and Drug Administration/European Medicines Agency safety alert based on emerging data from two ongoing phase III trials, reporting shorter survival in programmed death-ligand 1 (PD-L1)-negative patients receiving immunotherapy. Final results from these trials are unknown.
To compare survival in cisplatin-ineligible mUC patients receiving first-line immunotherapy versus those receiving carboplatin-based chemotherapy.
We conducted a retrospective cohort study of 2017 mUC patients receiving first-line carboplatin-based chemotherapy (n = 1530) or immunotherapy (n = 487) from January 1, 2011 to May 18, 2018 using the Flatiron Health electronic health record–derived database.
The primary outcomes were overall survival (OS), comparing 12- and 36-mo OS, and hazard ratios before and after 12 mo. Propensity score–based inverse probability of treatment weighting (IPTW) was used to address confounding in Kaplan-Meier and Cox regression model estimates of comparative effectiveness.
IPTW-adjusted OS rates in the immunotherapy group were lower at 12 mo (39.6% 95% confidence interval {CI} 34.0–45.3% vs 46.1% 95% CI 43.4–48.8%) but higher at 36 mo (28.3% 95% CI 21.8–34.7% vs 13.3% 95% CI 11.1–15.5%) relative to the chemotherapy group. Immunotherapy treatment demonstrated inferior OS during the first 12 mo relative to carboplatin-based chemotherapy (IPTW-adjusted hazard ratio HR 1.37, 95% CI 1.15–1.62), but superior OS beyond 12 mo (IPTW-adjusted HR 0.50, 95% CI 0.30–0.85). Limitations include retrospective design and potential unmeasured confounding.
In the setting of mUC, clinicians and patients should carefully consider how to balance the short-term benefit of chemotherapy against the long-term benefit of immunotherapy.
To determine the optimal first-line therapy for metastatic bladder cancer patients who are unfit for cisplatin, we compared carboplatin-based chemotherapy versus immunotherapy using real-world data. Survival in the 1st year of treatment was lower with immunotherapy relative to chemotherapy, but for patients surviving beyond the 1st year, immunotherapy was superior.
For cisplatin-ineligible metastatic urothelial carcinoma patients, we compared overall survival (OS) with first-line carboplatin-based chemotherapy versus immunotherapy. Immunotherapy demonstrated inferior 12-mo OS relative to carboplatin-based chemotherapy, but superior OS beyond 12 mo. Early benefits of chemotherapy must be balanced against late benefits of immunotherapy.
In this rare variant genetic association burden testing study of DNA repair genes, only BRCA2 was statistically significantly associated with localized prostate cancer and only in individuals of ...genetically determined European ancestry. Inherited mutations in the majority of DNA repair genes besides BRCA2 may not be associated with an increased risk of localized prostate cancer.
Identification of germline mutations in DNA repair genes has significant implications for the personalized treatment of individuals with prostate cancer (PrCa).
To determine DNA repair genes associated with localized PrCa in a diverse academic biobank and to determine genetic testing burden.
A cross-sectional study of 2391 localized PrCa patients was carried out.
Genetic ancestry and mutation rates (excluding somatic interference) in 17 DNA repair genes were determined in 1588 localized PrCa patients and 3273 cancer-free males. Burden testing within individuals of genetically determined European (EUR) and African (AFR) ancestry was performed between biobank PrCa cases and cancer-free biobank and gnomAD males.
AFR individuals with localized PrCa had lower DNA repair gene mutation rates than EUR individuals (1.4% vs 4.0%, p = 0.02). Mutation rates in localized PrCa patients were similar to those in biobank and gnomAD controls (EUR: 4.0% vs 2.8%, p = 0.15, vs 3.1%, p = 0.04; AFR: 1.4% vs 1.8%, p = 0.8, vs 2.1%, p = 0.5). Gene-based rare variant association testing revealed that only BRCA2 mutations were significantly enriched compared with gnomAD controls of EUR ancestry (1.0% vs 0.28%, p = 0.03). Of the participants, 21% and 11% met high-risk and very-high-risk criteria; of them, 3.7% and 6.2% had any germline genetic mutation and 1.0% and 2.5% had a BRCA2 mutation, respectively. Limitations of this study include an analysis of a relatively small, single-institution cohort.
DNA repair gene germline mutation rates are low in an academic biobank cohort of localized PrCa patients, particularly among individuals of AFR genetic ancestry. Mutation rates in genes with published evidence of association with PrCa exceed 2.5% only in high-risk, very-high-risk localized, and node-positive PrCa patients. These findings highlight the importance of risk stratification in localized PrCa patients to identify appropriate patients for germline genetic testing.
In the majority of patients who develop localized prostate cancer, germline genetic testing is unlikely to reveal an inherited DNA repair mutation, regardless of race. High-risk features increase the possibility of a germline DNA repair mutation.
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