Citations

Abstract Multiple myeloma (MM) is twice as common in African Americans (AA) compared to European Americans (EA). The reported familial clustering and the elevated MM risk among first-degree relatives of cases implicate genetic susceptibility. Previous genome-wide association studies (GWAS) in EA have identified 16 novel risk loci. In this study, we tested the generalizability of the established risk alleles to AA and conducted a meta-GWAS analysis using two sets of AA to identify additional novel common MM risk variants. In the first study, we genotyped 1,305 incident AA MM cases from the African American Multiple Myeloma Study (AAMMS) using the Illumina HumanCore GWAS array and compared them to 7,078 AA controls from the African Ancestry Prostate Cancer Consortium (AAPC) and African Ancestry Breast Cancer Consortium (AABC) using the Illumina 1M-Duo. In the second study, 95 additional AAMMS cases and 435 AA MM cases from the University of Arkansas for Medical Sciences (UAMS) were genotyped using the Illumina MegaBead Chip and compared to 2,390 AA controls from the Multiethnic Cohort. The Haplotype Reference Consortium (HRC) was used to impute the overlapping typed SNPS from each GWAS case and control set together. Per-allele risk associations were tested for 8,715,278 overlapping genotyped and imputed variants with >1% frequency and >0.8 imputation score using unconditional logistic regression in both sets, and the combined effects were estimated using a fixed-effect meta-analysis. Of the 16 reported risk loci discovered in EA, directional consistency was present for 15 variants; eight of these replicated at nominal significance p<0.05, with the most statistically significant variant being rs4487645 at 7p15.3 (OR=1.38, p=3.56×10-6). AA individuals with polygenic risk scores from these 16 variants (PRS) in the top 10% stratum had a 1.44-fold increased MM risk compared to those with a PRS in the 25th -75th percentiles. Additionally, we identified three suggestive novel loci located at 12q12, 9p24.3 and 9p13.1 at p<1×10-6, with ORs ranging from 1.25-1.55, but none reached genome-wide significance. The variant at 9p24.3 is located in an intron in the KANK1 gene and a correlated SNP in EAs (r2=0.5) is strongly associated with gene expression in neoplastic plasma cells (unpublished, Weinhold and Morgan). Our study replicated most of the reported risk loci discovered among EA, demonstrated that a PRS constructed using the 16 reported risk alleles was associated with MM risk, and provides suggestive evidence for additional loci associated with MM risk in AAs. Citation Format: Zhaohui Du, Chi Song, Kristin Rand, Niels Weinhold, David Van Den Berg, Amie Hwang, Xin Sheng, Victor Hom, Sikander Ailawadhi, Ajay K. Nooka, Seema Singhal, Karen Pawlish, Edward S. Peters, Cathryn Bock, Ann Mohrbacher, Alexander Stram, Sonja I. Berndt, William Blot, John David Carpten, Antoinette Stroup, Andrew Olshan, Wei Zhang, African Ancestry Breast & Prostate Consortium, Stephen Chanock, Jayesh Mehta, Graham A. Colditz, Jeffrey Wolf, Thomas G. Martin, Michael Tomasson, Mark A. Fiala, Howard Terebelo, Nalini Janakiraman, Laurence Kolonel, Loic LeMarchand, Elad Ziv, Daniel Stram, Ravi Vij, Leon Bernal-Mizrachi, Gareth J. Morgan, Jeffrey A. Zonder, Carol Ann Huff, Sagar Lonial, Robert Z. Orlowski, David V. Conti, Christopher A. Haiman, Wendy Cozen. A meta-analysis of genome-wide association studies of multiple myeloma among African Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 223.

Purpose: The aim of this study was to evaluate the ability of computer-aided detection (CAD) and human readers to detect pulmonary nodules ≥5 mm using 100 kV ultra–low-dose computed tomography (ULDCT) utilizing a tin filter. Materials and Methods: After informed consent, 55 patients prospectively underwent standard-dose chest CT (SDCT) using 120 kV followed by ULDCT using 100 kV/tin. Reference nodules ≥5 mm were identified by a thoracic radiologist using SDCT. Four thoracic radiologists marked detected nodules on SDCT and ULDCT examinations using a dedicated computer workstation. After a 6-month memory extinction, readers were shown the same ULDCT cases with all CAD markings as well as their original detections, and characterized CAD detections as true positive or false positive. Results: Volume CT Dose index (CTDIvol) for SDCT and ULDCT were 5.3±2 and 0.4±0.2 mGy (P<0.0001), respectively. Forty-five reference nodules were detected in 30 patients. Reader sensitivity varied widely but similarly for SDCT (ranging from 45% to 87%) and ULDCT (45% to 83%). CAD sensitivity was 76% (34/45) for SDCT and 71% (32/45) for ULDCT. After CAD, reader sensitivity substantially improved by 19% and 18% for 2 readers, and remained nearly unchanged for the other 2 readers (0% and 2%), despite reader perception that many more nodules were identified with CAD. There was a mean of 2 false-positive CAD detections/case. Conclusions: ULDCT with 100 kV/tin reduced patient dose by over 90% without compromising pulmonary nodule detection sensitivity. CAD can substantially improve nodule detection sensitivity at ULDCT for some readers, maintaining interobserver performance.

Genetic research generates results with implications for relatives. Recommendations addressing relatives’ access to a participant’s genetic research findings include eliciting participant preferences about access and choosing a representative to make decisions about access upon participant incapacity/death. Representatives are likely to be blood relatives or spouse/partners (who may share genetically related children). This raises the question of whether relatives hold similar attitudes about access or divergent attitudes that may yield conflict. We surveyed pancreatic cancer biobank participants (probands) and relatives in a family registry (blood relatives and spouse/partners of probands); 1,903 (>55%) surveys were returned. Results revealed few attitudinal differences between the groups. A slightly higher proportion of blood relatives agreed with statements reflecting proband privacy. In conclusion, probands’ decisions on access are likely to be accepted by relatives; in choosing a representative, probands may not face major differences in attitudes about privacy/sharing between a blood relative and a spouse/partner.

Key Points Biomarker scores generated after 1 week of steroid treatment of GVHD are prognostic. Biomarkers reflect prognosis better than early clinical response to GVHD treatment.

Abstract Background: Pembrolizumab (P), an anti-PD-1 immune checkpoint inhibitor, has been approved for treatment of microsatellite instability-high and mismatch repair deficient cancers. In I-SPY 2, patients were randomized to receive standard chemotherapy alone or in combination with an experimental agent. P was one of the experimental agents evaluated in HER2- patients in I-SPY 2 and graduated in the TN, HR+HER2-, and HER2- signatures. We hypothesize that a combination of two signatures predicting response to veliparib/carboplatin therapy in I-SPY 2 [MammaPrint High2 (MP2)/PARPi7-high] and reflecting DNA damage repair deficiency, may also predict response to P. In addition, we also tested 9 gene expression signatures reflecting different aspects of DNA damage and repair: FA, MMR, BER, HR, TLS, NER, NHEJ, DR, and DNA damage sensing (DDS) pathways. Methods: Data from 249 patients (P: 69 and controls: 180) were available. Pre-treatment biopsies were assayed using Agilent gene expression arrays. All I-SPY 2 qualifying biomarker analyses follow a pre-specified analysis plan. We used logistic modeling to assess biomarker performance. A biomarker is considered a specific predictor of P response if it associates with response in the P arm but not the control arm, and if the biomarker x treatment interaction is significant (likelihood ratio test, p&lt;0.05). This analysis is also performed adjusting for HR status as a covariate, and within receptor subsets, sample size permitting. For successful biomarkers, we use Bayesian modeling to estimate the pCR rates of 'predicted sensitive' patients in each arm. Our statistics are descriptive rather than inferential and do not adjust for multiplicities of other biomarkers outside this study. Results: MP2 status associates with pCR in P (OR=7.7; p=0.00021), but also to a lesser extent in the control arm (OR=2.4:p=0.045), with an OR ratio of 3.3 which trends toward significance, even after adjusting for HR status (LR p=0.083). A majority of TN patients are MP2; and TN/MP2 patients have an estimated pCR rate of 67% in P (vs. 23% in control). Although only ~30% of HR+HER2- patients were MP2, their estimated pCR rate in P is 61%, compared to 29% in unselected HR+/HER2- patients. PARPi7 predicted response in the P arm only in the HR+HER2- group (LR p= 0.025), but not in the population as a whole or the TN subtype. Combining MP2 and PARPi7 into MP2/PARPi7-high did not improve performance over MP2 as a single biomarker. Of the 9 DDR pathway signatures tested, both BER and DDS associate with pCR in P, but only DDS (which includes ATM, ATR, CHEK1-2) associates with pCR in the P arm (LR p=0.00029), and not the control arm (LR p=0.53), with a significant interaction with treatment (LR p=0.0064) that retains significance in a model adjusting for HR status. When dichotomized to optimize the biomarker x treatment interaction, the estimated pCR rate is 75% in P vs 18% in control, in the DDS+ subset. Conclusion: In this small study, MP2 status and a DNA damage sensing pathway but not the PARPi7 or other repair pathways show promise as predictive biomarkers for immune checkpoint inhibition therapy in breast cancer. Citation Format: Yau C, Wolf D, Brown-Swigart L, Hirst G, Sanil A, Singhrao R, I-SPY 2 TRIAL Investigators, Asare S, DeMichele A, Berry D, Esserman L, van 't Veer L, Nanda R, Liu M, Yee D. Analysis of DNA repair deficiency biomarkers as predictors of response to the PD1 inhibitor pembrolizumab: Results from the neoadjuvant I-SPY 2 trial for stage II-III high-risk breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD6-14.

Abstract Background: Pembrolizumab (Pembro), an anti-PD-1 immune checkpoint inhibitor, has been approved for the treatment of a variety of cancers including melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, and urothelial carcinoma. Pembro was recently evaluated in HER2- breast cancer patients in the neoadjuvant I-SPY 2 TRIAL and graduated in the triple negative (TN), HR+HER2-, and HER2- signatures. HER2- patients were randomized to receive Pembro+paclitaxel followed by doxorubicin/cyclophosphamide (P+T -&gt; AC) vs. T -&gt; AC. We and others have shown that TN breast cancers tend to have high numbers of immune infiltrates, including T cells and tumor associated macrophages (TAMs). We evaluated expression signatures representing 14 immune cell types (TILs, T cells, CD8 T cells, exhausted T cells, Th1, Tregs, cytotoxic cells, NK, NK CD56dim, dendritic cells, mast cells, B cells, macrophages, and neutrophils) as specific predictors of response to Pembro. Methods: Data from 248 patients (Pembro: 69; controls: 179) were available. Pre-treatment biopsies were assayed using Agilent gene expression arrays. Signature scores are calculated by averaging cell type specific genes. All I-SPY 2 qualifying biomarker analyses follow a pre-specified analysis plan. We used logistic modeling to assess biomarker performance. A biomarker is considered a specific predictor of Pembro response if it associates with response in the Pembro arm but not the control arm, and if the biomarker x treatment interaction is significant (likelihood ratio test, p&lt;0.05). This analysis is also performed adjusting for HR status as covariates, and within receptor subsets. For successful biomarkers, we use Bayesian modeling to estimate the pCR rates of 'predicted sensitive' patients in each arm. Our statistics are descriptive rather than inferential and do not adjust for multiplicities of other biomarkers outside this study. Results: 10 out of the 14 cell-type signatures tested are associated with response in the Pembro arm. Higher expression levels of 9 of these cell-type signatures are associated with higher pCR rates (T cells, exhausted T cells, Th1, cytotoxic cells, NK, NK CD56dim, dendritic cells, B cells, and macrophages), whereas higher mast cell signature expression is associated with non-pCR. Interestingly, many of these same signatures also associate or trend towards association with response in the control arm; and in a model adjusting for HR status, only 3 of these signatures (Th1, B cells and dendritic cells) show significant interaction with treatment. Within the whole population and the TN subtype, the dendritic cell signature is the strongest predictor of specific response to Pembro (OR/1SD: 4.04 and 4.4, LR p &lt; 0.001 overall and in TN). Although other immune signatures (T cells, exhausted T cells, NK, and macrophages) also associate with response in the Pembro arm in the TN subtype, only the dendritic cell and Th1 signatures have a significant interaction with treatment. In contrast, in the HR+HER2- subtype, only 3 signatures (Th1, B cells, and mast cells) associate with response to Pembro; but none of these signatures have significant interaction with treatment. Of note, in both the Pembro and control arms, HR+HER2- patients with higher average mast cell marker expression have lower pCR rates (OR/1SD: 0.33 and 0.51, LRp: 0.006 and 0.04 in Pembro and control arm). Conclusion: As expected, multiple immune cell expression signatures are predictive of response in the Pembro arm; but only dendritic cells and Th1 cells are specific to Pembro in both the population as a whole and the TN subtype. Interestingly, the presence of mast cells may impede response, especially in HR+HER2- patients. Correlation of these signatures with multiplex-IF immune markers is pending. Citation Format: Campbell M, Yau C, Borowsky A, Vandenberg S, Wolf D, Rimm D, Nanda R, Liu M, Brown-Swigart L, Hirst G, Asare S, van't Veer L, Yee D, DeMichele A, Berry D, Esserman L. Analysis of immune infiltrates (assessed via multiplex fluorescence immunohistochemistry) and immune gene expression signatures as predictors of response to the checkpoint inhibitor pembrolizumab in the neoadjuvant I-SPY 2 trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD6-08.

The aims of these experiments were to determine in vitro whether colonic distension releases acetylcholine, vasoactive intestinal polypeptide (VIP), and substance P in the guinea pig inferior mesenteric ganglia (IMG) and whether cholinergic and peptidergic mechanosensory nerves projecting from the colon to the IMG receive cholinergic input from other enteric neurons. Colonic distension significantly increased the release of [3H]-acetylcholine, VIP-like immunoreactivity, and substance P-like immunoreactivity in the IMG. Nicotinic receptor blockade in the colon diminished the increase in [3H]acetylcholine release, abolished the increase in VIP-like immunoreactivity release during distension, but had no effect on the release of substance P-like immunoreactivity. Nicotinic receptor blockade in the colon also decreased fast mechanosensory input and significantly reduced by 54% the slow excitatory postsynaptic potential amplitude evoked by colonic distension. The data suggest that enteric cholinergic and VIP mechanosensory neurons that project from the colon to sympathetic neurons in the IMG receive peripheral cholinergic input from other enteric neurons. There was no evidence for enteric cholinergic input to the mechanosensory substance P pathway.