Citations

BackgroundInducible co-stimulator (ICOS) is a CD28-related molecule exclusively expressed on activated T cells and plays a critical role in modulating the immune response in breast cancer. The blockage of ICOS pathway has been shown to inhibit the activity of Type 2 T helper cells, thus potentially protecting against cancer growth. The current study aims to investigate the correlation between inducible co-stimulator ligand (ICOSL) expression in tumor tissues and the prognoses of patients with invasive breast cancer.MethodsTumor samples from 562 Chinese patients with invasive breast carcinomas were collected between 2003 and 2010. The expression of ICOSL on breast tumor and adjacent non-cancerous tissue was determined via immunohistochemistry. The overall survival (OS) of patients with positive and negative ICOSL expression were described using Kaplan–Meier curves, respectively. Parametric correlation method was used to analyze the correlation between ICOSL expression and other clinicopathological parameters. ICOSL was selected as a dependent variable for multivariate analysis.ResultsPositive ICOSL expression was identified on the plasma membrane in both cytoplasm and the nucleus of breast cancer cells. Membrane-expressed ICOSL is determined as an independent prognostic factor for OS in breast cancer but without significantly correlating with other clinicopathologic parameters such as age, menopausal status, depth of invasion, lymph node metastasis status, histologic classification, etc.ConclusionOur study suggests that the up-regulated expression of ICOSL protein in breast tumor cells can be associated with poor prognoses in invasive breast carcinomas.

Abstract Background: Patients achieving a pathologic complete response (pCR) following neoadjuvant therapy have significantly improved event-free survival relative to those who do not; and pCR is an FDA-accepted endpoint to support accelerated approval of novel agents/combinations in the neoadjuvant treatment of high risk early stage breast cancer. Previous studies have shown that recurrence risk increased with increasing burden of residual disease (as assessed by the RCB index). As well, these studies suggest that patients with minimum residual disease (RCB-I class) also have favorable outcomes (comparable to those achieving a pCR) within high risk tumor subtypes. In this study, we assess whether integrating RCB with MRI functional tumor volume (FTV), which in itself is prognostic, can improve prediction of distant recurrence free survival (DRFS); and identify a subset of patients with minimal residual disease with comparable DRFS as those who achieved a pCR. Imaging tools can then be used to identify the subset that will do well early and guide the timing of surgical therapy. Method: We performed a pooled analysis of 596 patients from the I-SPY2 TRIAL with RCB, pre-surgical MRI FTV data and known follow-up (median 2.5 years). We first assessed whether FTV predicts residual disease (pCR or pCR/RCB-I) using ROC analysis. We applied a power transformation to normalize the pre-surgical FTV distribution; and assessed its association with DRFS using a bi-variate Cox proportional hazard model adjusting for HR/HER2 subtype. We also fitted a bivariate Cox model of RCB index adjusting for subtype; and assessed whether adding pre-surgical FTV to this model further improves association with DRFS using a likelihood ratio (LR) test. For the Cox modeling, penalized splines approximation of the transformed FTV and RCB index with 2 degrees of freedom was used to allow for non-linear effects of FTV and RCB on DRFS. Result: Pre-surgical MRI FTV is significantly associated with DRFS (Wald p<0.00001), and more effective at predicting pCR/RCB-I than predicting pCR alone (AUC: 0.72 vs. 0.65). Larger pre-surgical FTV remains associated with worse DRFS adjusting for subtype (Wald p <0.00001). The RCB index is also significantly associated with DRFS adjusting for subtype (Wald p<0.00001). Adding FTV to a model containing RCB and subtype further improves association with DRFS (LR p=0.0007). RCB-I patients have excellent DRFS (94% at 3 years compared to 95% in the pCR group). Efforts are underway to identify an optimal threshold for dichotomizing pre-surgical FTV and FTV change measures for use in combination with pCR/RCB-I class to generate integrated RCB (iRCB) groups as a composite predictor of DRFS. Conclusion: Pre-surgical MRI FTV is effective at predicting minimal residual disease (RCB0/I) in the I-SPY 2 TRIAL. Despite the association between FTV and RCB, FTV appears to provide independent added prognostic value (to RCB and subtype), suggesting that integrating MRI volume measures and RCB into a composite predictor may improve DRFS prediction. Citation Format: Hylton NM, Symmans WF, Yau C, Li W, Hatzis C, Isaacs C, Albain KS, Chen Y-Y, Krings G, Wei S, Harada S, Datnow B, Fadare O, Klein M, Pambuccian S, Chen B, Adamson K, Sams S, Mhawech-Fauceglia P, Magliocco A, Feldman M, Rendi M, Sattar H, Zeck J, Ocal I, Tawfik O, Grasso LeBeau L, Sahoo S, Vinh T, Yang S, Adams A, Chien AJ, Ferero-Torres A, Stringer-Reasor E, Wallace A, Boughey JC, Ellis ED, Elias AD, Lang JE, Lu J, Han HS, Clark AS, Korde L, Nanda R, Northfelt DW, Khan QJ, Viscusi RK, Euhus DM, Edmiston KK, Chui SY, Kemmer K, Wood WC, Park JW, Liu MC, Olopade O, Tripathy D, Moulder SL, Rugo HS, Schwab R, Lo S, Helsten T, Beckwith H, Haugen PK, van't Veer LJ, Perlmutter J, Melisko ME, Wilson A, Peterson G, Asare AL, Buxton MB, Paoloni M, Clennell JL, Hirst GL, Singhrao R, Steeg K, Matthews JB, Sanil A, Berry SM, Abe H, Wolverton D, Crane EP, Ward KA, Nelson M, Niell BL, Oh K, Brandt KR, Bang DH, Ojeda-Fournier H, Eghtedari M, Sheth PA, Bernreuter WK, Umphrey H, Rosen MA, Dogan B, Yang W, Joe B, I-SPY 2 TRIAL Consortium, Yee D, Pusztai L, DeMichele A, Asare SM, Berry DA, Esserman LJ. Refining neoadjuvant predictors of three year distant metastasis free survival: Integrating volume change as measured by MRI with residual cancer burden [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-07-03.

Abstract Background In clinically node-negative (cN0) breast cancer patients with triple negative (TN) and HER2+ disease and breast pathological complete response (breast pCR), low rates of nodal positivity after neoadjuvant chemotherapy (NAC) have been demonstrated. In these patients, the omission of surgical axillary staging has been proposed. However, this information is not routinely known preoperatively. We aimed to validate the correlation between pathologic breast response and pathologic nodal status, and evaluate the relationship between response of the breast tumor on MRI and pathologic nodal status after NAC in cN0 patients in the I-SPY2 trial. Methods We identified all patients with cT1-4 cN0 breast cancer prior to NAC from graduated arms of the I-SPY2 trial, a prospective neoadjuvant chemotherapy trial. Absence of residual disease post-NAC was defined as longest diameter (LD) of 0 mm on MRI. Breast pCR was defined as the absence of invasive tumor in the breast at surgery. Associations between ypN0 and patient, MRI, and tumor characteristics were assessed using chi-square tests and univariate regression. Results Of 365 cT1-4 cN0 patients included, 128 had HR+/HER2- tumors (35%), 60 HR+/HER2+ tumors (16%), 34 HR-/HER2+ tumors (9%) and 143 TN tumors (39%). Overall, 283 patients (78%) were ypN0 after NAC and 152 patients (42%) had a breast pCR. ypN0 rate was higher in patients with a breast pCR than those with residual disease (93% vs 66%, p<0.001). Patients with HR-/HER2+ and TN tumors were more likely to be ypN0 (97% and 87% respectively) than patients with HR+/HER2- and HR+/HER2+ disease (66% and 71% respectively, p<0.001). Other characteristics associated with ypN0 were tumor grade (grade I 57%, grade II 66%, grade III 84%; p=0.002), MammaPrint Classification (High Risk 1 68% and High Risk 2 87%; p<0.001) and absence of residual tumor in the breast on MRI (87% vs 72% in patients with evidence of tumor on MRI post-NAC/pre-surgery; p=0.003). In patients with HR-/HER2+, HR+/HER2+, HR-/HER2+ or TN disease and a breast pCR, ypN0 rate was respectively 82%, 96%, 96% and 97% (table 1). In patients with HR+/HER2-, HR+/HER2+, HR-/HER2+ or TN disease and with no evidence of residual disease in the breast on MRI, rate of ypN0 was 71%, 80%, 94% and 96% respectively. Conclusion In cT1-4 cN0 breast cancer patients with HR+/HER2+, HR-/HER2+ and TN tumors and a breast pCR, ypN0 rates after NAC are extremely high. In patients with HR-/HER2+ and TN tumors with no residual breast disease on MRI after NAC and pre-surgery, ypN0 rates are high enough to consider omission of axillary surgery. In patients with HR+ tumors, MRI is unsufficiently predictive for pathological response and can therefore not be used to select ypN0 patients. Research on the prediction of ypN0 in cN+ I-SPY2 patients is ongoing. Nodal status in patients with pCR and absence of residual disease on MRI Number of positive nodesBreast Cancer Subtype0123AllBreast pCR HR+/HER2-27(82)2(6)4(12)033(100)HR+/HER2+24(96)01(4)025(100)HR-/HER2+24(96)1(4)0025(100)TN67(97)2(3)0069(100)Absence of residual disease on MRI HR+/HER2-24(71)7(21)3(9)034(100)HR+/HER2+16(80)3(15)01(5)20(100)HR-/HER2+15(94)1(6)0016(100)TN54(96)2(4)0056(100) Citation Format: van der Noordaa ME, Esserman L, Yau C, Mukhtar R, Price E, Hylton N, Abe H, Wolverton D, Crane EP, Ward KA, Nelson M, Niell BL, Oh K, Brandt KR, Bang DH, Ojeda-Fournier H, Eghtedari M, Sheth PA, Bernreuter WK, Umphrey H, Rosen MA, Dogan B, Yang W, Joe B, van 't Veer L, Hirst G, Lancaster R, Wallace A, Alvaredo M, Symmans F, Asare S, Boughey JC, I-SPY2 Consortium. Role of breast MRI in predicting pathologically negative nodes after neoadjuvant chemotherapy in cN0 patients in the I-SPY2 trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD4-04.

Abstract Introduction: Atypical hyperplasia (also known as proliferative disease with atypia), while categorized as a benign finding, has been consistently associated with an increased risk of subsequent breast cancer that persists for decades after initial diagnosis. There are various other lesions that are classified as benign breast disease (BBD) that are routinely identified by pathologists that may also increase risk and be of use to inform breast cancer risk models. We sought to identify which BBD lesions were associated with increased risk of breast cancer in an African American (AA) cohort. Methods: Benign breast biopsies from 3,895 AA women diagnosed with BBD between 1997 and 2010 in metropolitan Detroit were reviewed for 12 benign features including columnar alterations, ductal ectasia, ductal hyperplasia, fibrosis, apocrine metaplasia, lobular hyperplasia, calcifications, cysts, intraductal papilloma, radial scar, sclerosing adenosis, and fibroadenomas. Women were followed for subsequent breast cancer using the Metropolitan Detroit Cancer Surveillance System, part of the Surveillance, Epidemiology, and End Results (SEER) cancer registry. Associations between BBD features and subsequent breast cancer were examined using chi-square tests. Features that had a significant chi-square test result were also combined into scores describing the overall number of BBD features identified, termed busy breast score. Multivariable log-binomial regression with backward selection based on BIC criteria was performed to assess risk ratio and 95% confidence intervals of breast cancer on 12 candidate features. Multivariable log-binomial regression was performed for busy breast score as well. All regression models were adjusted for age at biopsy and overall impression for presence of proliferative disease with or without atypia using non-proliferative disease as the reference. Models were checked for multicollinearity using a variable inflation factor (VIF). Results: Of the 3,895 AA women in the BBD cohort, 210 developed a subsequent breast cancer. The median age at biopsy among those without a subsequent cancer (controls) was 47 years of age, while cases were 53 years of age (p-value<0.001). In univariate analyses, ductal hyperplasia (p-value=0.001), lobular hyperplasia (p-value<0.001), calcifications (p-value<0.004), cysts (p-value=0.003), intra-ductal papilloma (p-value=0.005), sclerosing adenosis (p-value=0.002), columnar alterations (p-value<0.001) and radial scar (p-value=0.001) were associated with subsequent breast cancer. Fibroadenomas were inversely associated with subsequent breast cancer (p-value<0.001). In multivariable model after backwards selection, presence of columnar alterations was associated with increased risk of breast cancer, (RR=1.57, 95% CI: 1.16, 2.13). Combining the 9 BBD features associated with subsequent breast cancer in univariate analysis, those with a busy breast score of 5+ was associated with 2.5 times increased risk compared to those with none of these features (RR=2.52, 95% CI: 1.41, 4.49). As a continuous variable for busy breast score, each additional feature conferred a 20% increase in risk of breast cancer (RR=1.20, 95% CI: 1.10, 1.31). Conclusions: Columnar alterations confer increased risk of breast cancer beyond the risks associated with atypical hyperplasia, as does the presence of multiple types of BBD lesions in a single biopsy. These estimates may help improve the current risk assessment models for African American women and highlight the need for additional research regarding the utility of closer surveillance and potentially chemoprevention for reduction of breast cancer in these women. Citation Format: Michele L. Cote, Wei Chen, Julie J. Ruterbusch, Eman Abdulfatah, Visakha Pardeshi, Asra N. Shaik, Marcel T. Ghanim, MHD Fayez Daaboul, Daniel W. Visscher, Sudeshna Bandyopadhyay, Rouba Ali-Fehmi. Benign breast disease and subsequent breast cancer risk: The Detroit cohort. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr A25.

Abstract Reciprocal epithelial–mesenchymal interactions are pivotal in lung development, homeostasis, injury, and repair. Organoids have been used to investigate such interactions, but with a major focus on epithelial responses to mesenchyme and less attention to epithelial effects on mesenchyme. In the present study, we used nascent organoids composed of human and mouse lung epithelial and mesenchymal cells to demonstrate that healthy lung epithelium dramatically represses transcriptional, contractile, and matrix synthetic functions of lung fibroblasts. Repression of fibroblast activation requires signaling via the bone morphogenetic protein (BMP) pathway. BMP signaling is diminished after epithelial injury in vitro and in vivo, and exogenous BMP4 restores fibroblast repression in injured organoids. In contrast, inhibition of BMP signaling in healthy organoids is sufficient to derepress fibroblast matrix synthetic function. Our results reveal potent repression of fibroblast activation by healthy lung epithelium and a novel mechanism by which epithelial loss or injury is intrinsically coupled to mesenchymal activation via loss of repressive BMP signaling.

AbstractPurposeIt is unclear if a 3D transducer with the special design of mechanical swing or 2D array could provide acceptable 2D grayscale image quality for the general diagnosis purpose. The aim of this study is to compare the 2D image quality of a 3D intracavitary transducer with a conventional 2D intracavitary transducer using clinically relevant phantom experiments.MethodsAll measurements were performed on a GE Logiq E9 scanner with both a 2D (IC5‐9‐D) and a 3D (RIC5‐9‐D) transducer used in 2D mode. Selection of phantom targets and acquisition parameters were determined from analysis of 33 clinical pelvic exams. Depth of penetration (DOP), contrast response, contrast of anechoic cylinders (diameter: 6.7 mm) at 1.5 and 4.5 cm depths in transverse planes, and in‐plane resolution represented by full‐width half‐maximum of pin targets at multiple depths were measured with transmit frequencies of 7 and 8 MHz. Spherical signal‐noise‐ratio (SNR) (diameter: 4 and 2 mm) at multiple depths were measured at 8 MHz.ResultsRIC5‐9‐D demonstrated <8% decrease in DOP for both transmit frequencies (7 MHz: 69.7 ± 8.2 mm; 8 MHz: 64.3 ± 7.8 mm) compared with those from IC5‐9‐D (7 MHz: 73.9 ± 4.4 mm; 8 MHz: 69.4 ± 7.8 mm). A decreased anechoic contrast was observed with a 4.5 cm depth for RIC5‐9‐D (7 MHz: 23.2 ± 1.8 dB, P > 0.05; 8 MHz: 17.7 ± 0.9 dB, P < 0.01) compared with IC5‐9‐D (7 MHz: 25.9 ± 1.2 dB; 8 MHz: 21.5 ± 0.8 dB). The contrast response and spatial resolution performance were comparable between the two transducers. RIC5‐9‐D showed comparable SNR of anechoic spheres compared to IC5‐9‐D.Conclusions2D images from a 3D probe exhibited comparable overall image quality for routine clinical pelvic imaging.

AbstractRecent approvals of several oral targeted agents have revolutionized chronic lymphocytic leukemia (CLL) therapy. However, CLL patients continue to progress; particularly, 4% to 20% of previously treated CLL patients undergo transformation into high-grade lymphoma. Richter transformation is defined as a transformation of CLL into aggressive lymphoma, most commonly diffuse large B-cell lymphoma. These patients typically have poor response to traditional chemotherapy used to treat de novo diffuse large B-cell lymphoma and similar or shorter overall survival (median 3-11 months) in the era of novel agents. Here, I review the contemporary literature on Richter transformation, particularly in the context of novel agents used in CLL, and discuss the management approach for these patients.

Objective This study aims for targeted biopsy validation of magnetic resonance fingerprinting (MRF) and diffusion mapping for characterizing peripheral zone (PZ) prostate cancer and noncancers. Materials and Methods One hundred four PZ lesions in 85 patients who underwent magnetic resonance imaging were retrospectively analyzed with apparent diffusion coefficient (ADC) mapping, MRF, and targeted biopsy (cognitive or in-gantry). A radiologist blinded to pathology drew regions of interest on targeted lesions and visually normal peripheral zone on MRF and ADC maps. Mean T1, T2, and ADC were analyzed using linear mixed models. Generalized estimating equations logistic regression analyses were used to evaluate T1 and T2 relaxometry combined with ADC in differentiating pathologic groups. Results Targeted biopsy revealed 63 cancers (low-grade cancer/Gleason score 6 = 10, clinically significant cancer/Gleason score ≥7 = 53), 15 prostatitis, and 26 negative biopsies. Prostate cancer T1, T2, and ADC (mean ± SD, 1660 ± 270 milliseconds, 56 ± 20 milliseconds, 0.70 × 10−3 ± 0.24 × 10−3 mm2/s) were significantly lower than prostatitis (mean ± SD, 1730 ± 350 milliseconds, 77 ± 36 milliseconds, 1.00 × 10−3 ± 0.30 × 10−3 mm2/s) and negative biopsies (mean ± SD, 1810 ± 250 milliseconds, 71 ± 37 milliseconds, 1.00 × 10−3 ± 0.33 × 10−3 mm2/s). For cancer versus prostatitis, ADC was sensitive and T2 specific with comparable area under curve (AUC; (AUCT2 = 0.71, AUCADC = 0.79, difference between AUCs not significant P = 0.37). T1 + ADC (AUCT1 + ADC = 0.83) provided the best separation between cancer and negative biopsies. Low-grade cancer T2 and ADC (mean ± SD, 75 ± 29 milliseconds, 0.96 × 10−3 ± 0.34 × 10−3 mm2/s) were significantly higher than clinically significant cancers (mean ± SD, 52 ± 16 milliseconds, 0.65 ± 0.18 × 10−3 mm2/s), and T2 + ADC (AUCT2 + ADC = 0.91) provided the best separation. Conclusions T1 and T2 relaxometry combined with ADC mapping may be useful for quantitative characterization of prostate cancer grades and differentiating cancer from noncancers for PZ lesions seen on T2-weighted images.