A Contemporary Review of Immune Checkpoint Inhibitors in Advanced Clear Cell Renal Cell Carcinoma.

The use of checkpoint inhibitors in advanced and metastatic renal cell carcinomas (RCCs) has rapidly evolved over the past several years. While immune-oncology (IO) drug therapy has been successful at resulting in improved responses and survival, combination therapies with immune checkpoint inhibitors and vascular endothelial growth factor (VEGF) inhibitors have further improved outcomes. This article reviews the landmark trials that have led to the approval of IO therapies, including the Checkmate 214 trial and combination IO/VEGF TKI therapies with Checkmate 9ER, CLEAR, and Keynote-426, and it includes a discussion on promising therapies moving in the future.

The effect of anticoagulation on clinical outcomes in novel Coronavirus (COVID-19) pneumonia in a U.S. cohort.

BACKGROUND: COVID-19 infection is associated with D-dimer elevations, high rates of thrombus formation, and poor clinical outcomes. We sought to determine if empiric therapeutic anticoagulation (AC) affected survival in COVID-19 patients compared to standard prophylactic AC. METHODS: Retrospective analysis of 402 COVID-19 patients hospitalized between March 15 and May 31, 2020 was performed. Clinical outcomes were compared between 152 patients treated with therapeutic AC to 250 patients on prophylactic AC. An elastic net logistic regression was designed to first identify the important variables affecting mortality. These variables were then included as covariates to AC in standard multivariate logistic regression models studying the effect of AC on death. Nonparametric survival analysis was conducted, and Kaplan Meier curves were constructed. RESULTS: Increased mortality was associated with therapeutic AC [OR 3.42 (2.06, 5.67)]. The log-rank test was statistically significant at p = 0.001 showing higher mortality for patients treated with therapeutic AC compared to prophylactic AC. Subset analysis of critically ill and intubated patients had similar survival curves regardless of AC dose. The log-rank test was not significant even with Prentice modification. For non-ICU patients, the log rank test favoring prophylactic AC disappeared when the analysis was stratified by D-dimer level less or greater than 3 µg/mL. Approximately 9% of patients receiving therapeutic AC experienced clinically significant bleeding or thrombocytopenia, versus 3% in those receiving prophylactic AC. CONCLUSIONS: In our cohort, therapeutic anticoagulation provided no mortality benefit over thromboprophylaxis, independent of co-morbidities or disease severity. More adverse events were observed with therapeutic AC.

Polygenic risk score for the prediction of breast cancer is related to lesser terminal duct lobular unit involution of the breast.

Terminal duct lobular units (TDLUs) are the predominant anatomical structures where breast cancers originate. Having lesser degrees of age-related TDLU involution, measured as higher TDLUs counts or more epithelial TDLU substructures (acini), is related to increased breast cancer risk among women with benign breast disease (BBD). We evaluated whether a recently developed polygenic risk score (PRS) based on 313-common variants for breast cancer prediction is related to TDLU involution in the background, normal breast tissue, as this could provide mechanistic clues on the genetic predisposition to breast cancer. Among 1398 women without breast cancer, higher values of the PRS were significantly associated with higher TDLU counts (P = 0.004), but not with acini counts (P = 0.808), in histologically normal tissue samples from donors and diagnostic BBD biopsies. Mediation analysis indicated that TDLU counts may explain a modest proportion (≤10%) of the association of the 313-variant PRS with breast cancer risk. These findings suggest that TDLU involution might be an intermediate step in the association between common genetic variation and breast cancer risk.

Relationship Between Hereditary Cancer Syndromes and Oncotype DX Recurrence Score.

BACKGROUND: Oncotype DX (ODX) is a genomic assay of tumor tissue that is utilized to predict the likelihood of recurrence and benefit of chemotherapy in breast cancer patients. Five to 10% of breast cancers are hereditary, and hereditary syndromes may not be uncovered through family history alone. We hypothesized that high ODX recurrence score (RS) may signal a potential hereditary cancer risk. PATIENTS AND METHODS: We performed a retrospective analysis of data from hormone receptor-positive breast cancer patients who had undergone ODX and germline genetic testing. The chi-square test and Fisher exact test were used to examine univariable association between RS and germline mutation status. Multivariable logistic regression was utilized to examine if there was an association of RS with germline mutation status. RESULTS: In univariable analysis, the association of RS with germline mutation status was significant (P < .0001). In the multivariable logistic regression model predicting germline mutation status, RS level remained significantly associated with germline mutation, in particular BRCA1 or BRCA2. The mean RS for those with non-BRCA1/2 germline mutations versus those without germline mutations was not significant (P = .38). CONCLUSION: High RS is associated with germline mutation status. Breast cancer patients with high RS are more likely to harbor a mutation in the BRCA1 or BRCA2 genes. If confirmed prospectively, oncologists may consider referring patients with high RS for genetic risk assessment and counseling to inform management plans, as well as counseling of family members.

Association between breast cancer genetic susceptibility variants and terminal duct lobular unit involution of the breast.

Terminal duct lobular units (TDLUs) are the predominant source of future breast cancers, and lack of TDLU involution (higher TDLU counts, higher acini count per TDLU and the product of the two) is a breast cancer risk factor. Numerous breast cancer susceptibility single nucleotide polymorphisms (SNPs) have been identified, but whether they are associated with TDLU involution is unknown. In a pooled analysis of 872 women from two studies, we investigated 62 established breast cancer SNPs and relationships with TDLU involution. Poisson regression models with robust variance were used to calculate adjusted per-allele relative risks (with the non-breast cancer risk allele as the referent) and 95% confidence intervals between TDLU measures and each SNP. All statistical tests were two-sided; P < 0.05 was considered statistically significant. Overall, 36 SNPs (58.1%) were related to higher TDLU counts although this was not statistically significant (p = 0.25). Six of the 62 SNPs (9.7%) were nominally associated with at least one TDLU measure: rs616488 (PEX14), rs11242675 (FOXQ1) and rs6001930 (MKL1) were associated with higher TDLU count (p = 0.047, 0.045 and 0.031, respectively); rs1353747 (PDE4D) and rs6472903 (8q21.11) were associated with higher acini count per TDLU (p = 0.007 and 0.027, respectively); and rs1353747 (PDE4D) and rs204247 (RANBP9) were associated with the product of TDLU and acini counts (p = 0.024 and 0.017, respectively). Our findings suggest breast cancer SNPs may not strongly influence TDLU involution. Agnostic genome-wide association studies of TDLU involution may provide new insights on its biologic underpinnings and breast cancer susceptibility.

Ages at menarche- and menopause-related genetic variants in relation to terminal duct lobular unit involution in normal breast tissue.

Reduced levels of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini per TDLU, have been associated with higher breast cancer risk. Younger age at menarche and older age at menopause have been previously related to lower levels of TDLU involution. To determine a possible genetic link, we examined whether single-nucleotide polymorphisms (SNPs) previously established in genome-wide association studies (GWAS) for ages at menarche and menopause are associated with TDLU involution. We conducted a pooled analysis of 862 women from two studies. H&E tissue sections were assessed for numbers of TDLUs and acini/TDLU. Poisson regression models were used to estimate associations of 36 menarche- and 21 menopause-SNPs with TDLU counts, acini counts/TDLU, and the product of these two measures, adjusting for age and study site. Fourteen percent of evaluated SNPs (eight SNPs) were associated with TDLU counts at p < 0.05, suggesting an enrichment of associations with TDLU counts. However, only menopause-SNPs had >50 % that were either significantly or nonsignificantly associated with TDLU measures in the directions consistent with their relationships shown in GWAS. Among ten SNPs that were statistically significantly associated with at least one TDLU involution measure (p < 0.05), seven SNPs (rs466639: RXRG; rs2243803: SLC14A2; rs2292573: GAB2; rs6438424: 3q13.32; rs7606918: METAP1D; rs11668344: TMEM150B; rs1635501: EXO1) were associated in the consistent directions. Our data suggest that the loci associated with ages at menarche and menopause may influence TDLU involution, suggesting some shared genetic mechanisms. However, larger studies are needed to confirm the results.

Relation of Serum Estrogen Metabolites with Terminal Duct Lobular Unit Involution Among Women Undergoing Diagnostic Image-Guided Breast Biopsy.

Higher levels of circulating estrogens and estrogen metabolites (EMs) have been associated with higher breast cancer risk. In breast tissues, reduced levels of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini per TDLU, have also been linked to elevated breast cancer risk. However, it is unknown whether reduced TDLU involution mediates the risk associated with circulating EMs. In a cross-sectional analysis of 94 premenopausal and 92 postmenopausal women referred for clinical breast biopsy at an academic facility in Vermont, we examined the associations of 15 EMs, quantified using liquid chromatography-tandem mass spectrometry, with the number of TDLUs and acini count/TDLU using zero-inflated Poisson regression with a robust variance estimator and ordinal logistic regression models, respectively. All analyses were stratified by menopausal status and adjusted for potential confounders. Among premenopausal women, comparing the highest vs. the lowest tertiles, levels of unconjugated estradiol (risk ratio (RR) = 1.74, 95 % confidence interval (CI) = 1.06-2.87, p trend = 0.03), 2-hydroxyestrone (RR = 1.74, 95 % CI = 1.01-3.01, p trend = 0.04), and 4-hydroxyestrone (RR = 1.74, 95 % CI = 0.99-3.06, p trend = 0.04) were associated with significantly higher TDLU count. Among postmenopausal women, higher levels of estradiol (RR = 2.09, 95 % CI = 1.01-4.30, p trend = 0.04) and 16α-hydroxyestrone (RR = 2.27, 95 % CI = 1.29-3.99, p trend = 0.02) were significantly associated with higher TDLU count. Among postmenopausal women, higher levels of EMs, specifically conjugated estrone and 2- and 4-pathway catechols, were also associated with higher acini count/TDLU. Our data suggest that higher levels of serum EMs are generally associated with lower levels of TDLU involution.

Circulating insulin-like growth factor-I, insulin-like growth factor binding protein-3 and terminal duct lobular unit involution of the breast: a cross-sectional study of women with benign breast disease.

BACKGROUND: Terminal duct lobular units (TDLUs) are the primary structures from which breast cancers and their precursors arise. Decreased age-related TDLU involution and elevated mammographic density are both correlated and independently associated with increased breast cancer risk, suggesting that these characteristics of breast parenchyma might be linked to a common factor. Given data suggesting that increased circulating levels of insulin-like growth factors (IGFs) factors are related to reduced TDLU involution and increased mammographic density, we assessed these relationships using validated quantitative methods in a cross-sectional study of women with benign breast disease. METHODS: Serum IGF-I, IGFBP-3 and IGF-I:IGFBP-3 molar ratios were measured in 228 women, ages 40-64, who underwent diagnostic breast biopsies yielding benign diagnoses at University of Vermont affiliated centers. Biopsies were assessed for three separate measures inversely related to TDLU involution: numbers of TDLUs per unit of tissue area ("TDLU count"), median TDLU diameter ("TDLU span"), and number of acini per TDLU ("acini count"). Regression models, stratified by menopausal status and adjusted for potential confounders, were used to assess the associations of TDLU count, median TDLU span and median acini count per TDLU with tertiles of circulating IGFs. Given that mammographic density is associated with both IGF levels and breast cancer risk, we also stratified these associations by mammographic density. RESULTS: Higher IGF-I levels among postmenopausal women and an elevated IGF-I:IGFBP-3 ratio among all women were associated with higher TDLU counts, a marker of decreased lobular involution (P-trend = 0.009 and <0.0001, respectively); these associations were strongest among women with elevated mammographic density (P-interaction <0.01). Circulating IGF levels were not significantly associated with TDLU span or acini count per TDLU. CONCLUSIONS: These results suggest that elevated IGF levels may define a sub-group of women with high mammographic density and limited TDLU involution, two markers that have been related to increased breast cancer risk. If confirmed in prospective studies with cancer endpoints, these data may suggest that evaluation of IGF signaling and its downstream effects may have value for risk prediction and suggest strategies for breast cancer chemoprevention through inhibition of the IGF system.

Relationship of Terminal Duct Lobular Unit Involution of the Breast with Area and Volume Mammographic Densities.

Elevated mammographic density (MD) is an established breast cancer risk factor. Reduced involution of terminal duct lobular units (TDLU), the histologic source of most breast cancers, has been associated with higher MD and breast cancer risk. We investigated relationships of TDLU involution with area and volumetric MD, measured throughout the breast and surrounding biopsy targets (perilesional). Three measures inversely related to TDLU involution (TDLU count/mm(2), median TDLU span, median acini count/TDLU) assessed in benign diagnostic biopsies from 348 women, ages 40-65, were related to MD area (quantified with thresholding software) and volume (assessed with a density phantom) by analysis of covariance, stratified by menopausal status and adjusted for confounders. Among premenopausal women, TDLU count was directly associated with percent perilesional MD (P trend = 0.03), but not with absolute dense area/volume. Greater TDLU span was associated with elevated percent dense area/volume (P trend<0.05) and absolute perilesional MD (P = 0.003). Acini count was directly associated with absolute perilesional MD (P = 0.02). Greater TDLU involution (all metrics) was associated with increased nondense area/volume (P trend ≤ 0.04). Among postmenopausal women, TDLU measures were not significantly associated with MD. Among premenopausal women, reduced TDLU involution was associated with higher area and volumetric MD, particularly in perilesional parenchyma. Data indicating that TDLU involution and MD are correlated markers of breast cancer risk suggest that associations of MD with breast cancer may partly reflect amounts of at-risk epithelium. If confirmed, these results could suggest a prevention paradigm based on enhancing TDLU involution and monitoring efficacy by assessing MD reduction.

Circulating sex hormones and terminal duct lobular unit involution of the normal breast.

BACKGROUND: Terminal duct lobular units (TDLU) are the predominant source of breast cancers. Lesser degrees of age-related TDLU involution have been associated with increased breast cancer risk, but factors that influence involution are largely unknown. We assessed whether circulating hormones, implicated in breast cancer risk, are associated with levels of TDLU involution using data from the Susan G. Komen Tissue Bank (KTB) at the Indiana University Simon Cancer Center (2009-2011). METHODS: We evaluated three highly reproducible measures of TDLU involution, using normal breast tissue samples from the KTB (n = 390): TDLU counts, median TDLU span, and median acini counts per TDLU. RRs (for continuous measures), ORs (for categorical measures), 95% confidence intervals (95% CI), and Ptrends were calculated to assess the association between tertiles of estradiol, testosterone, sex hormone-binding globulin (SHBG), progesterone, and prolactin with TDLU measures. All models were stratified by menopausal status and adjusted for confounders. RESULTS: Among premenopausal women, higher prolactin levels were associated with higher TDLU counts (RRT3vsT1:1.18; 95% CI: 1.07-1.31; Ptrend = 0.0005), but higher progesterone was associated with lower TDLU counts (RRT3vsT1: 0.80; 95% CI: 0.72-0.89; Ptrend < 0.0001). Among postmenopausal women, higher levels of estradiol (RRT3vsT1:1.61; 95% CI: 1.32-1.97; Ptrend < 0.0001) and testosterone (RRT3vsT1: 1.32; 95% CI: 1.09-1.59; Ptrend = 0.0043) were associated with higher TDLU counts. CONCLUSIONS: These data suggest that select hormones may influence breast cancer risk potentially through delaying TDLU involution. IMPACT: Increased understanding of the relationship between circulating markers and TDLU involution may offer new insights into breast carcinogenesis. Cancer Epidemiol Biomarkers Prev; 23(12); 2765-73. ©2014 AACR.

Terminal duct lobular unit involution of the normal breast: implications for breast cancer etiology.

BACKGROUND: Greater degrees of terminal duct lobular unit (TDLU) involution have been linked to lower breast cancer risk; however, factors that influence this process are poorly characterized. METHODS: To study this question, we developed three reproducible measures that are inversely associated with TDLU involution: TDLU counts, median TDLU span, and median acini counts/TDLU. We determined factors associated with TDLU involution using normal breast tissues from 1938 participants (1369 premenopausal and 569 postmenopausal) ages 18 to 75 years in the Susan G. Komen Tissue Bank at the Indiana University Simon Cancer Center. Multivariable zero-inflated Poisson models were used to estimate relative risks (RRs) and 95% confidence intervals (95% CIs) for factors associated with TDLU counts, and multivariable ordinal logistic regression models were used to estimate odds ratios (ORs) and 95% CIs for factors associated with categories of median TDLU span and acini counts/TDLU. RESULTS: All TDLU measures started declining in the third age decade (all measures, two-sided P trend ≤ .001); and all metrics were statistically significantly lower among postmenopausal women. Nulliparous women demonstrated lower TDLU counts compared with uniparous women (among premenopausal women, RR = 0.79, 95% CI = 0.73 to 0.85; among postmenopausal, RR = 0.67, 95% CI = 0.56 to 0.79); however, rates of age-related TDLU decline were faster among parous women. Other factors were related to specific measures of TDLU involution. CONCLUSION: Morphometric analysis of TDLU involution warrants further evaluation to understand the pathogenesis of breast cancer and assessing its role as a progression marker for women with benign biopsies or as an intermediate endpoint in prevention studies.

Quantitative Analysis of TDLUs using Adaptive Morphological Shape Techniques.

Within the complex branching system of the breast, terminal duct lobular units (TDLUs) are the anatomical location where most cancer originates. With aging, TDLUs undergo physiological involution, reflected in a loss of structural components (acini) and a reduction in total number. Data suggest that women undergoing benign breast biopsies that do not show age appropriate involution are at increased risk of developing breast cancer. To date, TDLU assessments have generally been made by qualitative visual assessment, rather than by objective quantitative analysis. This paper introduces a technique to automatically estimate a set of quantitative measurements and use those variables to more objectively describe and classify TDLUs. To validate the accuracy of our system, we compared the computer-based morphological properties of 51 TDLUs in breast tissues donated for research by volunteers in the Susan G. Komen Tissue Bank and compared results to those of a pathologist, demonstrating 70% agreement. Secondly, in order to show that our method is applicable to a wider range of datasets, we analyzed 52 TDLUs from biopsies performed for clinical indications in the National Cancer Institute's Breast Radiology Evaluation and Study of Tissues (BREAST) Stamp Project and obtained 82% correlation with visual assessment. Lastly, we demonstrate the ability to uncover novel measures when researching the structural properties of the acini by applying machine learning and clustering techniques. Through our study we found that while the number of acini per TDLU increases exponentially with the TDLU diameter, the average elongation and roundness remain constant.