The emergence of immunotherapy has dramatically changed how non–small cell lung cancer is treated, and longer survival is now possible for some patients, even those with advanced disease. Although ...some patients achieve durable responses to checkpoint blockade, not all experience such benefits, and some suffer from significant immunotoxicities. Given this, biomarkers that predict response to therapy are essential, and testing for tumor programmed death ligand 1(PD‐L1) expression is the current standard. The extent of PD‐L1 expression determined by immunohistochemistry (IHC) has demonstrated a correlation with treatment response, although limitations with this marker exist. Recently, tumor mutational burden has emerged as an alternative biomarker, and studies have demonstrated its utility, irrespective of the PD‐L1 level of a tumor. Gene expression signatures, tumor genotype (such as the presence of an oncogenic driver mutation), as well as the density of tumor‐infiltrating lymphocytes in the tumor microenvironment also seem to affect response to immunotherapy and are being researched. Peripheral serum markers are being studied, and some have demonstrated predictive ability, although most are still investigational and need prospective validation. In the current article, the authors review the biomarker PD‐L1 as well as other emerging and investigational tissue‐based and serum‐based markers that have potential to better predict responders to immunotherapy.
Immunotherapy has dramatically changed how advanced non–small cell lung cancer is treated, and longer survival is now possible for some patients, although not all patients benefit from these agents, and some suffer toxicities, highlighting the importance of biomarkers that predict efficacy. This article reviews several biomarkers, including programmed death ligand 1, as well as other emerging and investigational tissue‐based and serum‐based markers that have potential to better predict responders to checkpoint inhibition.
Immunotherapy has revolutionized the field of oncology. By inhibiting the cytotoxic T-lymphocyte-associated protein (CTLA-4) and programmed death-1 (PD-1) immune checkpoint pathways, multiple studies ...have demonstrated greatly improved survival in locally advanced and metastatic cancers including melanoma, renal, lung, gastric, and hepatocellular carcinoma. Trials in other malignancies are ongoing, and undoubtedly the number of drugs in this space will grow beyond the six currently approved by the Food and Drug Administration. However, by altering the immune response to fight cancer, a new class of side effects has emerged known as immune-related adverse events (irAEs). These adverse events are due to overactivation of the immune system in almost any organ of the body, and can occur at any point along a patient's treatment course. irAEs such as endocrinopathies (thyroiditis), colitis, and pneumonitis may occur more commonly. However, other organs such as the liver, heart, or brain may also be affected by immune overactivation and any of these side effects may become life threatening. This review presents an approach to promptly recognize and manage these toxicities, to hopefully minimize morbidity and mortality from irAEs.
Microsatellite instability‐high (MSI‐H) and tumor mutational burden (TMB) are predictive biomarkers for immune‐checkpoint inhibitors (ICIs). Still, the relationship between the underlying cause(s) of ...MSI and TMB in tumors remains poorly defined. We investigated associations of TMB to mismatch repair (MMR) protein expression patterns by immunohistochemistry (IHC) and MMR mutations in a diverse sample of tumors. Hypothesized differences were identified by the protein/gene affected/mutated and the tumor histology/primary site. Overall, 1057 MSI‐H tumors were identified from the 32 932 tested. MSI was examined by NGS using 7000+ target microsatellite loci. TMB was calculated using only nonsynonymous missense mutations sequenced with a 592‐gene panel; a subset of MSI‐H tumors also had MMR IHC performed. Analyses examined TMB by MMR protein heterodimer impacted (loss of MLH1/PMS2 vs. MSH2/MSH6 expression) and gene‐specific mutations. The sample was 54.6% female; mean age was 63.5 years. Among IHC tested tumors, loss of co‐expression of MLH1/PMS2 was more common (n = 544/705, 77.2%) than loss of MSH2/MSH6 (n = 81/705, 11.5%; P < .0001), and was associated with lower mean TMB (MLH1/PMS2: 25.03 mut/Mb vs MSH2/MSH6 46.83 mut/Mb; P < .0001). TMB also varied by tumor histology: colorectal cancers demonstrating MLH1/PMS2 loss had higher TMBs (33.14 mut/Mb) than endometrial cancers (20.60 mut/Mb) and other tumors (25.59 mut/Mb; P < .0001). MMR gene mutations were detected in 42.0% of tumors; among these, MSH6 mutations were most common (25.7%). MSH6 mutation patterns showed variability by tumor histology and TMB. TMB varies by underlying cause(s) of MSI and tumor histology; this heterogeneity may contribute to differences in response to ICI.
What's new?
Immunotherapy based on checkpoint inhibitors shows promising results in a variety of cancer types, but still benefits a minority of patients. High microsatellite instability (MSI) and tumor mutational burden (TMB) have both been identified as biomarkers predictive of response to checkpoint inhibitors. Here, the authors investigated how the underlying causes of MSI influence TMB. Tumors lacking the mismatch repair protein duo MLH1/PMS2 had lower TMB than those lacking a different protein heterodimer, MLH2/MSH6. Even among tumors lacking the same mismatch repair proteins, the tissue of origin influenced mutational burden.
Opinion statement
The standard of care in patients with early-stage non-small cell lung cancer (NSCLC) following surgical resection has been adjuvant chemotherapy for the last two decades, despite ...modest improvements in survival and high rates of disease recurrence. Numerous clinical trials have reported practice-changing findings demonstrating a benefit in disease-free survival (DFS) or event-free survival (EFS) with perioperative immunotherapy. This has led to several recent regulatory approvals supporting the use of adjuvant immunotherapy or neoadjuvant immuno-chemotherapy in NSCLC, and such therapies are now an integral component of care for early-stage disease. However, in select cases, such as in the presence of certain tumor oncogenes associated with immunotherapy resistance, the use of checkpoint inhibitors in the perioperative setting should generally be avoided. This speaks to the importance of integrating routine tissue-based molecular profiling, that evaluates for tumor oncogene mutations and PD-L1 expression, into our practice when caring for patients with early-stage NSCLC. While an overall survival (OS) advantage has yet to be firmly established from many of the recent studies evaluating perioperative immunotherapy, it is expected that an OS benefit and higher rates of cure will become evident as these data mature, especially among patients with greater levels of tumor PD-L1 expression.
Recent work on the determinants of obesity has shown a positive association between household food insecurity and overweight status in adult women, yet research exploring this issue in children has ...been inconclusive. In this study we examine the association between food insecurity and overweight status in young school children by using a large, nationally representative sample.
Data from the Early Childhood Longitudinal Study-Kindergarten Cohort (ECLS-K) were analyzed. Replicate heights and weights were measured on kindergarten children (N = 16889) in the spring of 1999. Children with a body mass index > or = 95th percentile of their gender-specific BMI-for-age chart were considered overweight. Food-insecurity status was assessed by using the full 18-question US Department of Agriculture Household Food Security Scale. Multivariate logistic regression was used to assess the relationship between overweight and food-insecurity status while controlling for potential demographic, socioeconomic, and behavioral confounders.
Overall, 11.2% of the girls and 11.8% of the boys were overweight. Children from food-insecure households were 20% less likely to be overweight than their food-secure counterparts. Similar results on the food-insecurity/overweight link were found across a range of different models and expressions for key variables. Positive predictors of overweight status included low physical activity, television watching for > 2 hours/day, high birth weight, black or Latino ethnicity, and low income.
There are strong arguments for reducing food insecurity among households with young children. This research suggests that these arguments would be based on reasons other than a potential link to obesity. Low activity levels and excessive television watching, however, were strongly related to overweight status, a finding that supports continued efforts to intervene in these areas.
Research on neighborhood food access has focused on documenting disparities in the food environment and on assessing the links between the environment and consumption. Relatively few studies have ...combined in-store food availability measures with geographic mapping of stores. We review research that has used these multi-dimensional measures of access to explore the links between the neighborhood food environment and consumption or weight status. Early research in California found correlations between red meat, reduced-fat milk, and whole-grain bread consumption and shelf space availability of these products in area stores. Subsequent research in New York confirmed the low-fat milk findings. Recent research in Baltimore has used more sophisticated diet assessment tools and store-based instruments, along with controls for individual characteristics, to show that low availability of healthy food in area stores is associated with low-quality diets of area residents. Our research in southeastern Louisiana has shown that shelf space availability of energy-dense snack foods is positively associated with BMI after controlling for individual socioeconomic characteristics. Most of this research is based on cross-sectional studies. To assess the direction of causality, future research testing the effects of interventions is needed. We suggest that multi-dimensional measures of the neighborhood food environment are important to understanding these links between access and consumption. They provide a more nuanced assessment of the food environment. Moreover, given the typical duration of research project cycles, changes to in-store environments may be more feasible than changes to the overall mix of retail outlets in communities.
Previous studies on the relationship of dietary intake to the neighbourhood food environment have focused on access to supermarkets, quantified by geographic distance or store concentration measures. ...However, in-store food availability may also be an important determinant, particularly for urban neighbourhoods with a greater concentration of small food stores. This study synthesises both types of information - store access and in-store availability - to determine their potential relationship to fruit and vegetable consumption.
Residents in four census tracts were surveyed in 2001 about their fruit and vegetable intake. Household distances to food stores in these and surrounding tracts were obtained using geographical information system mapping techniques. In-store fruit and vegetable availability was measured by linear shelf space. Multivariate linear regression models were used to measure the association of these neighbourhood availability measures with consumption.
Four contiguous census tracts in central-city New Orleans.
A random sample of 102 households.
Greater fresh vegetable availability within 100 m of a residence was a positive predictor of vegetable intake; each additional metre of shelf space was associated with 0.35 servings per day of increased intake. Fresh fruit availability was not associated with intake, although having a small food store within this same distance was a marginal predictor of fruit consumption.
The findings suggest the possible importance of small neighbourhood food stores and their fresh produce availability in affecting fruit and vegetable intake.
Several studies have examined associations between the food retail environment and obesity, though virtually no work has been done in the urban South, where obesity rates are among the highest in the ...country. This study assessed associations between access to food retail outlets and obesity in New Orleans. Data on individual characteristics and body weight were collected by telephone interviews from a random sample of adults (
N
= 3,925) living in New Orleans in 2004–2005. The neighborhood of each individual was geo-mapped by creating a 2-km buffer around the center point of the census tract in which they lived. Food retailer counts were created by summing the total number of each food store type and fast food establishment within this 2-km neighborhood. Hierarchical linear models assessed associations between access to food retailers and obesity status. After adjusting for individual characteristics, each additional supermarket in a respondent’s neighborhood was associated with a reduced odds for obesity (OR 0.93, 95% CI 0.88–0.99). Fast food restaurant (OR 1.01, 95% CI 1.00–1.02) and convenience store (OR 1.01, 95% CI 1.00–1.02) access were each predictive of greater obesity odds. An individual’s access to food stores and fast food restaurants may play a part in determining weight status. Future studies with longitudinal and experimental designs are needed to test whether modifications in the food environment may assist in the prevention of obesity.
Environmental approaches to the obesity problem in the US have garnered favor due to growing evidence that changes to the environment are at the root of the epidemic. Low-income urban neighborhoods, ...where obesity rates are disproportionately high, typically lack supermarkets yet have a high density of small food stores. This may increase the risk for unhealthy diets and obesity for neighborhood residents, because small stores carry mostly energy-dense foods and few fruits and vegetables. This paper pulls together various studies and pilot work conducted in New Orleans to explore the rationale behind small store interventions. Many low-income residents in New Orleans live within walking distance of small food stores and shop at them frequently. Marketing research has documented that changes to in-store shelf space and displays of specific foods affect the sales of these foods. Initiatives in New Orleans and elsewhere have demonstrated some success with improving healthy food availability in small stores, and an intercept survey of customers at small stores suggests that customers would purchase more fruits and vegetables if available. Efforts to encourage small store operators to offer a healthier mix of foods may, in the end, depend on the profitability of such changes. Evidence from a typical small store in New Orleans indicates that a greater percentage of gross profits come from snack foods and beverages than from fruits and vegetables. More research is needed to better understand the financial operations of small food stores and whether altering the mix of foods is economically feasible.
Purpose
Prior data suggest driver-mutated NSCLC, especially EGFR and ALK tumors, poorly respond to immunotherapy. However, little research using real-world cohorts have been performed, nor is it ...clear whether PD-L1 and smoking history are predictive of outcomes in such tumors. This study assessed rwPFS in a large cohort with driver-mutated advanced NSCLC treated with single-agent PD-1/PDL-1 inhibitors.
Methods
Real-world data from 1746 patients were analyzed and rwPFS with immunotherapy was determined for EGFR, ALK, BRAF, and KRAS tumors. Kaplan–Meier curves characterized rwPFS and correlated with PD-L1 and smoking history. Comparisons were tested using log-rank.
Results
Median rwPFS and the percent progression-free at 12 months were greater among KRAS (3.3 months, 21.1%) and BRAF (3.6 months, 20.6%) as compared to EGFR (2.5 months, 8.1%) and ALK tumors (2.3 months, 11.2%). KRAS tumors with PD-L1 ≥ 1% had longer rwPFS than PD-L1 < 1% tumors (4.1 versus 3.2 months,
p
= 0.001). PD-L1 positivity did not predict rwPFS in EGFR, ALK, or BRAF tumors. However, a smoking history was associated with longer rwPFS in EGFR (2.6 versus 2.3 months,
p
= 0.048) and ALK tumors (3.0 versus 2.1 months,
p
= 0.049) as compared to no smoking history.
Conclusion
Real-world PFS with immunotherapy was greater in KRAS and BRAF as compared to EGFR and ALK tumors. PD-L1 positivity was predictive in KRAS and not associated with rwPFS in other mutation types. While median rwPFS was short for EGFR and ALK tumors, small subsets were progression-free at 12 months. Better characterizing these subsets that benefit, along with developing strategies to overcome immunotherapy resistance in EGFR/ALK tumors are needed.
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