ECOG-ACRIN EAZ171: Prospective Validation Trial of Germline Predictors of Taxane-Induced Peripheral Neuropathy in Black Women With Early-Stage Breast Cancer.

PURPOSE: Black women experience higher rates of taxane-induced peripheral neuropathy (TIPN) compared with White women when receiving adjuvant once weekly paclitaxel for early-stage breast cancer, leading to more dose reductions and higher recurrence rates. EAZ171 aimed to prospectively validate germline predictors of TIPN and compare rates of TIPN and dose reductions in Black women receiving (neo)adjuvant once weekly paclitaxel and once every 3 weeks docetaxel for early-stage breast cancer. METHODS: Women with early-stage breast cancer who self-identified as Black and had intended to receive (neo)adjuvant once weekly paclitaxel or once every 3 weeks docetaxel were eligible, with planned accrual to 120 patients in each arm. Genotyping was performed to determine germline neuropathy risk. Grade 2-4 TIPN by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 was compared between high- versus low-risk genotypes and between once weekly paclitaxel versus once every 3 weeks docetaxel within 1 year. Patient-rated TIPN and patient-reported outcomes were compared using patient-reported outcome (PRO)-CTCAE and Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity. RESULTS: Two hundred and forty of 249 enrolled patients had genotype data, and 91 of 117 (77.8%) receiving once weekly paclitaxel and 87 of 118 (73.7%) receiving once every 3 weeks docetaxel were classified as high-risk. Physician-reported grade 2-4 TIPN was not significantly different in high- versus low-risk genotype groups with once weekly paclitaxel (47% v 35%; P = .27) or with once every 3 weeks docetaxel (28% v 19%; P = .47). Grade 2-4 TIPN was significantly higher in the once weekly paclitaxel versus once every 3 weeks docetaxel arm by both physician-rated CTCAE (45% v 29%; P = .02) and PRO-CTCAE (40% v 24%; P = .03). Patients receiving once weekly paclitaxel required more dose reductions because of TIPN (28% v 9%; P < .001) or any cause (39% v 25%; P = .02). CONCLUSION: Germline variation did not predict risk of TIPN in Black women receiving (neo)adjuvant once weekly paclitaxel or once every 3 weeks docetaxel. Once weekly paclitaxel was associated with significantly more grade 2-4 TIPN and required more dose reductions than once every 3 weeks docetaxel.

Germline predictors for bevacizumab induced hypertensive crisis in ECOG-ACRIN 5103 and BEATRICE.

BACKGROUND: Bevacizumab is a beneficial therapy in several advanced cancer types. Predictive biomarkers to better understand which patients are destined to benefit or experience toxicity are needed. Associations between bevacizumab induced hypertension and survival have been reported but with conflicting conclusions. METHODS: We performed post-hoc analyses to evaluate the association in 3124 patients from two phase III adjuvant breast cancer trials, E5103 and BEATRICE. Differences in invasive disease-free survival (IDFS) and overall survival (OS) between patients with hypertension and those without were compared. Hypertension was defined as systolic blood pressure (SBP) ≥ 160 mmHg (n = 346) and SBP ≥ 180 mmHg (hypertensive crisis) (n = 69). Genomic analyses were performed to evaluate germline genetic predictors for the hypertensive crisis. RESULTS: Hypertensive crisis was significantly associated with superior IDFS (p = 0.015) and OS (p = 0.042), but only IDFS (p = 0.029; HR = 0.28) remained significant after correction for prognostic factors. SBP ≥ 160 mmHg was not associated with either IDFS or OS. A common single-nucleotide polymorphism, rs6486785, was significantly associated with hypertensive crisis (p = 8.4 × 10-9; OR = 5.2). CONCLUSION: Bevacizumab-induced hypertensive crisis is associated with superior outcomes and rs6486785 predicted an increased risk of this key toxicity.

Critical Role of Novel O-GlcNAcylation of S550 and S551 on the p65 Subunit of NF-κB in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with a mere 5-year survival of ~10%. This highlights the urgent need for innovative treatment options for PDAC patients. The nuclear factor κB (NF-κB) is a crucial transcription factor that is constitutively activated in PDAC. It mediates the transcription of oncogenic and inflammatory genes that facilitate multiple PDAC phenotypes. Thus, a better understanding of the mechanistic underpinnings of NF-κB activation holds great promise for PDAC diagnosis and effective therapeutics. Here, we report a novel finding that the p65 subunit of NF-κB is O-GlcNAcylated at serine 550 and 551 upon NF-κB activation. Importantly, the overexpression of either serine-to-alanine (S-A) single mutant (S550A or S551A) or double mutant (S550A/S551A) of p65 in PDAC cells impaired NF-κB nuclear translocation, p65 phosphorylation, and transcriptional activity, independent of IκBα degradation. Moreover, the p65 mutants downregulate a category of NF-κB-target genes, which play a role in perpetuating major cancer hallmarks. We further show that overexpression of the p65 mutants inhibited cellular proliferation, migration, and anchorage-independent growth of PDAC cells compared to WT-p65. Collectively, we discovered novel serine sites of p65 O-GlcNAcylation that drive NF-κB activation and PDAC phenotypes, thus opening new avenues by inhibiting the NF-κB O-GlcNAcylation enzyme, O-GlcNAc transferase (OGT), for PDAC treatment in the future.

Genetic Regulation of Human isomiR Biogenesis.

MicroRNAs play a critical role in regulating gene expression post-transcriptionally. Variations in mature microRNA sequences, known as isomiRs, arise from imprecise cleavage and nucleotide substitution or addition. These isomiRs can target different mRNAs or compete with their canonical counterparts, thereby expanding the scope of miRNA post-transcriptional regulation. Our study investigated the relationship between cis-acting single-nucleotide polymorphisms (SNPs) in precursor miRNA regions and isomiR composition, represented by the ratio of a specific 5'-isomiR subtype to all isomiRs identified for a particular mature miRNA. Significant associations between 95 SNP-isomiR pairs were identified. Of note, rs6505162 was significantly associated with both the 5'-extension of hsa-miR-423-3p and the 5'-trimming of hsa-miR-423-5p. Comparison of breast cancer and normal samples revealed that the expression of both isomiRs was significantly higher in tumors than in normal tissues. This study sheds light on the genetic regulation of isomiR maturation and advances our understanding of post-transcriptional regulation by microRNAs.

Cytochrome P450 Oxidoreductase (POR) Associated with Severe Paclitaxel-Induced Peripheral Neuropathy in Patients of European Ancestry from ECOG-ACRIN E5103.

PURPOSE: Paclitaxel is a widely used anticancer therapeutic. Peripheral neuropathy is the dose-limiting toxicity and negatively impacts quality of life. Rare germline gene markers were evaluated for predicting severe taxane-induced peripheral neuropathy (TIPN) in the patients of European ancestry. In addition, the impact of Cytochrome P450 (CYP) 2C8, CYP3A4, and CYP3A5 metabolizer status on likelihood of severe TIPN was also assessed. EXPERIMENTAL DESIGN: Whole-exome sequencing analyses were performed in 340 patients of European ancestry who received a standard dose and schedule of paclitaxel in the adjuvant, randomized phase III breast cancer trial, E5103. Patients who experienced grade 3-4 (n = 168) TIPN were compared to controls (n = 172) who did not experience TIPN. For the analyses, rare variants with a minor allele frequency ≤ 3% and predicted to be deleterious by protein prediction programs were retained. A gene-based, case-control analysis using SKAT was performed to identify genes that harbored an imbalance of deleterious variants associated with increased risk of severe TIPN. CYP star alleles for CYP2C8, CYP3A4, and CYP3A5 were called. An additive logistic regression model was performed to test the association of CYP2C8, CYP3A4, and CYP3A5 metabolizer status with severe TIPN. RESULTS: Cytochrome P450 oxidoreductase (POR) was significantly associated with severe TIPN (P value = 1.8 ×10-6). Six variants were predicted to be deleterious in POR. There were no associations between CYP2C8, CYP3A4, or CYP3A5 metabolizer status with severe TIPN. CONCLUSIONS: Rare variants in POR predict an increased risk of severe TIPN in patients of European ancestry who receive paclitaxel.

Inhibition of PRMT5 by market drugs as a novel cancer therapeutic avenue.

Market drugs, such as Food and Drug Administration (FDA) or European Medicines Agency (EMA)-approved drugs for specific indications provide opportunities for repurposing for newer therapeutics. This potentially saves resources invested in clinical trials that verify drug safety and tolerance in humans prior to alternative indication approval. Protein arginine methyltransferase 5 (PRMT5) overexpression has been linked to promoting the tumor phenotype in several cancers, including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and breast cancer (BC), making PRMT5 an important target for cancer therapy. Previously, we showed that PRMT5-mediated methylation of the nuclear factor (NF)-κB, partially contributes to its constitutive activation observed in cancers. In this study, we utilized an AlphaLISA-based high-throughput screening method adapted in our lab, and identified one FDA-approved drug, Candesartan cilexetil (Can, used in hypertension treatment) and one EMA-approved drug, Cloperastine hydrochloride (Clo, used in cough treatment) that had significant PRMT5-inhibitory activity, and their anti-tumor properties were validated using cancer phenotypic assays in vitro. Furthermore, PRMT5 selective inhibition of methyltransferase activity was confirmed by reduction of both NF-κB methylation and its subsequent activation upon drug treatment. Using in silico prediction, we identified critical residues on PRMT5 targeted by these drugs that may interfere with its enzymatic activity. Finally, Clo and Can treatment have exhibited marked reduction in tumor growth in vivo. Overall, we provide basis for pursuing repurposing Clo and Can as anti-PRMT5 cancer therapies. Our study offers potential safe and fast repurposing of previously unknown PRMT5 inhibitors into clinical practice.

Osteocyte Egln1/Phd2 links oxygen sensing and biomineralization via FGF23.

Osteocytes act within a hypoxic environment to control key steps in bone formation. FGF23, a critical phosphate-regulating hormone, is stimulated by low oxygen/iron in acute and chronic diseases, however the molecular mechanisms directing this process remain unclear. Our goal was to identify the osteocyte factors responsible for FGF23 production driven by changes in oxygen/iron utilization. Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHI) which stabilize HIF transcription factors, increased Fgf23 in normal mice, as well as in osteocyte-like cells; in mice with conditional osteocyte Fgf23 deletion, circulating iFGF23 was suppressed. An inducible MSC cell line ('MPC2') underwent FG-4592 treatment and ATACseq/RNAseq, and demonstrated that differentiated osteocytes significantly increased HIF genomic accessibility versus progenitor cells. Integrative genomics also revealed increased prolyl hydroxylase Egln1 (Phd2) chromatin accessibility and expression, which was positively associated with osteocyte differentiation. In mice with chronic kidney disease (CKD), Phd1-3 enzymes were suppressed, consistent with FGF23 upregulation in this model. Conditional loss of Phd2 from osteocytes in vivo resulted in upregulated Fgf23, in line with our findings that the MPC2 cell line lacking Phd2 (CRISPR Phd2-KO cells) constitutively activated Fgf23 that was abolished by HIF1α blockade. In vitro, Phd2-KO cells lost iron-mediated suppression of Fgf23 and this activity was not compensated for by Phd1 or -3. In sum, osteocytes become adapted to oxygen/iron sensing during differentiation and are directly sensitive to bioavailable iron. Further, Phd2 is a critical mediator of osteocyte FGF23 production, thus our collective studies may provide new therapeutic targets for skeletal diseases involving disturbed oxygen/iron sensing.

A non-coding GWAS variant impacts anthracycline-induced cardiotoxic phenotypes in human iPSC-derived cardiomyocytes.

Anthracyclines, widely used to treat breast cancer, have the potential for cardiotoxicity. We have previously identified and validated a germline single nucleotide polymorphism, rs28714259, associated with an increased risk of anthracycline-induced heart failure. We now provide insights into the mechanism by which rs28714259 might confer increased risk of cardiac damage. Using hiPSC-derived cardiomyocyte cell lines with either intrinsic polymorphism or CRISPR-Cas9-mediated deletion of rs28714259 locus, we demonstrate that glucocorticoid receptor signaling activated by dexamethasone pretreatment prior to doxorubicin exposure preserves cardiomyocyte viability and contractility in cardiomyocytes containing the major allele. Homozygous loss of the rs28714259 major allele diminishes dexamethasone's protective effect. We further demonstrate that the risk allele of rs28714259 disrupts glucocorticoid receptor and rs28714259 binding affinity. Finally, we highlight the activation of genes and pathways involved in cardiac hypertrophy signaling that are blocked by the risk allele, suggesting a decreased adaptive survival response to doxorubicin-related stress.

Passage number affects differentiation of sensory neurons from human induced pluripotent stem cells.

Induced pluripotent stem cells (iPSCs) are a valuable resource for neurological disease-modeling and drug discovery due to their ability to differentiate into neurons reflecting the genetics of the patient from which they are derived. iPSC-derived cultures, however, are highly variable due to heterogeneity in culture conditions. We investigated the effect of passage number on iPSC differentiation to optimize the generation of sensory neurons (iPSC-dSNs). Three iPSC lines reprogrammed from the peripheral blood of three donors were differentiated into iPSC-dSNs at passage numbers within each of the following ranges: low (5-10), intermediate (20-26), and high (30-38). Morphology and pluripotency of the parent iPSCs were assessed prior to differentiation. iPSC-dSNs were evaluated based on electrophysiological properties and expression of key neuronal markers. All iPSC lines displayed similar morphology and were similarly pluripotent across passage numbers. However, the expression levels of neuronal markers and sodium channel function analyses indicated that iPSC-dSNs differentiated from low passage numbers better recapitulated the sensory neuron phenotype than those differentiated from intermediate or high passage numbers. Our results demonstrate that lower passage numbers may be better suited for differentiation into peripheral sensory neurons.

Using VBIM Technique to Discover ARMC4/ODAD2 as a Novel Negative Regulator of NF-κB and a New Tumor Suppressor in Colorectal Cancer.

Since nuclear factor (NF) κB plays pivotal roles in inflammation and cancer, understanding its regulation holds great promise for disease therapy. Using the powerful validation-based insertional mutagenesis (VBIM) technique established by us previously, we discovered armadillo repeat-containing protein 4 (ARMC4)/outer dynein arm docking complex subunit 2 (ODAD2), a rarely studied protein known to date, as a novel negative regulator of NF-κB in colorectal cancer (CRC). High expression of ARMC4 downregulated the expression of NF-κB-dependent genes, dramatically reduced NF-κB activity, cellular proliferation, anchorage-independent growth, and migratory ability in vitro, and significantly decreased xenograft tumor growth in vivo. Co-immunoprecipitation experiments demonstrated that ARMC4 forms a complex with NF-κB. Importantly, the lower ARMC4 expression in patient tumors than normal tissues indicates its potential tumor suppressor function in CRC. Collectively, we uncovered a completely new facet of ARMC4 function by identifying it as a novel NF-κB negative regulator, thus uncovering ARMC4 as a potential new therapeutic target in CRC.

Impact of African ancestry on the relationship between body mass index and survival in an early-stage breast cancer trial (ECOG-ACRIN E5103).

BACKGROUND: African ancestry (AA) and obesity are associated with worse survival in early-stage breast cancer. Obesity disproportionately affects women of AA; however, the intersection between ancestry and obesity on breast cancer outcomes remains unclear. METHODS: A total of 2854 patients in the adjuvant trial E5103 were analyzed. Genetic ancestry was determined using principal components from a genome-wide array. The impact of continuous or binary body mass index (BMI) on disease-free survival (DFS) and overall survival (OS) was evaluated by multivariable Cox proportional hazards models in AA patients and European ancestry (EA) patients. RESULTS: There were 2471 EA patients and 383 AA patients. Higher BMI was significantly associated with worse DFS and OS only in AA patients (DFS hazard ratio [HR], 1.25; 95% CI, 1.07-1.46; OS HR, 1.38; 95% CI, 1.10-1.73), not in EA patients (DFS HR, 0.97; 95% CI, 0.90-1.05; OS HR, 1.03; 95% CI, 0.93-1.14). Severe obesity (BMI ≥40) was significantly associated with worse survival in AA patients (DFS HR, 2.04; 95% CI, 1.21-3.43; OS HR, 2.21; 95% CI, 1.03-4.75) but had no impact on that of EA patients. In the estrogen receptor-positive (ER+) and triple-negative breast cancer subgroups, BMI was significantly associated with worse outcomes only in those AA patients with ER+ disease. Within the AA group, BMI remained associated with worse survival regardless of the AA proportion. CONCLUSIONS: Higher BMI was statistically significantly associated with worse breast cancer outcomes in AA but not EA patients. This association was most significant for severe obesity and those with ER+ disease. These observations help define optimal populations for weight change interventions designed to affect disparities and survival in early-stage breast cancer. LAY SUMMARY: African ancestry and obesity are both risk factors for worse survival after early-stage breast cancer. Women of African descent are also disproportionately affected by obesity; however, it is unclear what impact body weight has on racial disparities in breast cancer. Data from a large phase 3 clinical trial in high-risk, early-stage breast cancer were used to determine how body weight affects survival outcomes in European versus African Americans. Study results demonstrate that a higher body mass index is associated with increased risk of breast cancer recurrence and worse survival in women of African ancestry but not in women of European ancestry.

The impact of SBF2 on taxane-induced peripheral neuropathy.

Taxane-induced peripheral neuropathy (TIPN) is a devastating survivorship issue for many cancer patients. In addition to its impact on quality of life, this toxicity may lead to dose reductions or treatment discontinuation, adversely impacting survival outcomes and leading to health disparities in African Americans (AA). Our lab has previously identified deleterious mutations in SET-Binding Factor 2 (SBF2) that significantly associated with severe TIPN in AA patients. Here, we demonstrate the impact of SBF2 on taxane-induced neuronal damage using an ex vivo model of SBF2 knockdown of induced pluripotent stem cell-derived sensory neurons. Knockdown of SBF2 exacerbated paclitaxel changes to cell viability and neurite outgrowth while attenuating paclitaxel-induced sodium current inhibition. Our studies identified paclitaxel-induced expression changes specific to mature sensory neurons and revealed candidate genes involved in the exacerbation of paclitaxel-induced phenotypes accompanying SBF2 knockdown. Overall, these findings provide ex vivo support for the impact of SBF2 on the development of TIPN and shed light on the potential pathways involved.

Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients.

BACKGROUND: Hypertension and proteinuria are common bevacizumab-induced toxicities. No validated biomarkers are available for identifying patients at risk of these toxicities. METHODS: A genome-wide association study (GWAS) meta-analysis was performed in 1039 bevacizumab-treated patients of European ancestry in four clinical trials (CALGB 40502, 40503, 80303, 90401). Grade ≥2 hypertension and proteinuria were recorded (CTCAE v.3.0). Single-nucleotide polymorphism (SNP)-toxicity associations were determined using a cause-specific Cox model adjusting for age and sex. RESULTS: The most significant SNP associated with hypertension with concordant effect in three out of the four studies (p-value <0.05 for each study) was rs6770663 (A > G) in KCNAB1, with the G allele increasing the risk of hypertension (p-value = 4.16 × 10-6). The effect of the G allele was replicated in ECOG-ACRIN E5103 in 582 patients (p-value = 0.005). The meta-analysis of all five studies for rs6770663 led to p-value = 7.73 × 10-8, close to genome-wide significance. The most significant SNP associated with proteinuria was rs339947 (C > A, between DNAH5 and TRIO), with the A allele increasing the risk of proteinuria (p-value = 1.58 × 10-7). CONCLUSIONS: The results from the largest study of bevacizumab toxicity provide new markers of drug safety for further evaluations. SNP in KCNAB1 validated in an independent dataset provides evidence toward its clinical applicability to predict bevacizumab-induced hypertension. ClinicalTrials.gov Identifier: NCT00785291 (CALGB 40502); NCT00601900 (CALGB 40503); NCT00088894 (CALGB 80303) and NCT00110214 (CALGB 90401).

BRE12-158: A Postneoadjuvant, Randomized Phase II Trial of Personalized Therapy Versus Treatment of Physician's Choice for Patients With Residual Triple-Negative Breast Cancer.

PURPOSE: Patients with triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy (NAC) have high risk of recurrence with prior data suggesting improved outcomes with capecitabine. Targeted agents have demonstrated activity across multiple cancer types. BRE12-158 was a phase II, multicenter trial that randomly allocated patients with TNBC with residual disease after NAC to genomically directed therapy versus treatment of physician choice (TPC). PATIENTS AND METHODS: From March 2014 to December 2018, 193 patients were enrolled. Residual tumors were sequenced using a next-generation sequencing test. A molecular tumor board adjudicated all results. Patients were randomly allocated to four cycles of genomically directed therapy (arm A) versus TPC (arm B). Patients without a target were assigned to arm B. Primary end point was 2-year disease-free survival (DFS) among randomly assigned patients. Secondary/exploratory end points included distant disease-free survival, overall survival, toxicity assessment, time-based evolution of therapy, and drug-specific outcomes. RESULTS: One hundred ninety-three patients were randomly allocated or were assigned to arm B. The estimated 2-year DFS for the randomized population only was 56.6% (95% CI, 0.45 to 0.70) for arm A versus 62.4% (95% CI, 0.52 to 0.75) for arm B. No difference was seen in DFS, distant disease-free survival, or overall survival for the entire or randomized populations. There was increased uptake of capecitabine for TPC over time. Patients randomly allocated later had less distant recurrences. Circulating tumor DNA status remained a significant predictor of outcome with some patients demonstrating clearance with postneoadjuvant therapy. CONCLUSION: Genomically directed therapy was not superior to TPC for patients with residual TNBC after NAC. Capecitabine should remain the standard of care; however, the activity of other agents in this setting provides rationale for testing optimal combinations to improve outcomes. Circulating tumor DNA should be considered a standard covariate for trials in this setting.

Profiling of Adipose and Skeletal Muscle in Human Pancreatic Cancer Cachexia Reveals Distinct Gene Profiles with Convergent Pathways.

The vast majority of patients with pancreatic ductal adenocarcinoma (PDAC) suffer cachexia. Although cachexia results from concurrent loss of adipose and muscle tissue, most studies focus on muscle alone. Emerging data demonstrate the prognostic value of fat loss in cachexia. Here we sought to identify the muscle and adipose gene profiles and pathways regulated in cachexia. Matched rectus abdominis muscle and subcutaneous adipose tissue were obtained at surgery from patients with benign conditions (n = 11) and patients with PDAC (n = 24). Self-reported weight loss and body composition measurements defined cachexia status. Gene profiling was done using ion proton sequencing. Results were queried against external datasets for validation. 961 DE genes were identified from muscle and 2000 from adipose tissue, demonstrating greater response of adipose than muscle. In addition to known cachexia genes such as FOXO1, novel genes from muscle, including PPP1R8 and AEN correlated with cancer weight loss. All the adipose correlated genes including SCGN and EDR17 are novel for PDAC cachexia. Pathway analysis demonstrated shared pathways but largely non-overlapping genes in both tissues. Age related muscle loss predominantly had a distinct gene profiles compared to cachexia. This analysis of matched, externally validate gene expression points to novel targets in cachexia.

Methylomic Signatures of High Grade Serous Ovarian Cancer.

High-grade serous ovarian cancer (HGSOC) harbours aberrant epigenetic features, including DNA methylation. In this study we delineate pathways and networks altered by DNA methylation and associated with HGSOC initiation and progression to a platinum-resistant state. By including tumours from patients who had been treated with the hypomethylating agent (HMA) guadecitabine, we also addressed the role of HMAs in treatment of HGSOC. Tumours from patients with primary (platinum-naïve) HGSOC (n = 20) were compared to patients with recurrent platinum-resistant HGSOC and enrolled in a recently completed clinical trial (NCT01696032). Human ovarian surface epithelial cells (HOSE; n = 5 samples) served as normal controls. Genome-wide methylation profiles were determined. DNA methyltransferase (DNMT) expression levels were examined by immunohistochemistry and correlated with clinical outcomes. Cancer-related and tumorigenesis networks were enriched among differentially methylated genes (DMGs) in primary OC vs. HOSE. When comparing platinum-resistant and primary tumours, 452 CpG island (CGI)-containing gene promoters acquired DNA methylation; of those loci, decreased (P < 0.01) methylation after HMA treatment was observed in 42% (n = 189 CGI). Stem cell pluripotency and cytokine networks were enriched in recurrent platinum-resistant OC tumours, while drug metabolism and transport-related networks were downregulated in tumours from HMA-treated patients compared to HOSE. Lower DNMT1 and 3B protein levels in pre-treatment tumours were associated with improved progression-free survival. The findings provide important insight into the DNA methylation landscape of HGSOC tumorigenesis, platinum resistance and epigenetic resensitization. Epigenetic reprogramming plays an important role in HGSOC aetiology and contributes to clinical outcomes.

Impact of Body Mass Index on Presence of ctDNA and Disease Recurrence after Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer: Analysis from BRE12-158.

PURPOSE: This retrospective analysis aimed to determine the relationship between body mass index (BMI) and circulating tumor DNA (ctDNA) in triple-negative breast cancer (TNBC), and to evaluate the impact of BMI on disease recurrence and survival in the homogeneous, high-risk population of patients with residual TNBC after neoadjuvant chemotherapy. EXPERIMENTAL DESIGN: BRE12-158 was a phase II trial of genomically directed therapy versus physician's choice in residual TNBC after chemotherapy. ctDNA was isolated from plasma samples, and categorized as positive or negative. BMI (kg/m2) after surgery was analyzed as both a continuous and categorical variable: normal weight, <25; overweight, 25-30; and obese, ≥30. We compared ctDNA category and BMI, and estimated probability of disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS) by BMI. RESULTS: Of 177 patients in BRE12-158, 172 had BMI and 140 had ctDNA data. There was no difference in mean BMI between those with ctDNA positivity versus negativity (P = 0.48). There was no relationship between BMI category and presence of ctDNA (P = 0.31). In multivariate analysis, continuous BMI was not prognostic of DDFS (P = 0.996), DFS (P = 0.41), or OS (P = 0.98). There was no association between BMI categories and survival (P = 0.92, 0.74, and 0.97 for DDFS, DFS, and OS, respectively). CONCLUSIONS: In patients with residual TNBC after neoadjuvant chemotherapy, BMI was not prognostic of DDFS, DFS, or OS. There was no signal of a relationship between BMI and presence of ctDNA. This suggests inherent aggressive tumor biology, in which host phenotype may have less influence and impact of weight loss interventions may be diminished.