Abstract
Background: Breast ultrasound identifies additional carcinomas not detected in mammography, but has a higher rate of false-positive findings which result in more unnecessary breast biopsies. ...Shear-Wave Elastography (SWE), an ultrasound technique used to quantify the stiffness of a lesion, showed promising results to improve the diagnostic performance of B-mode breast ultrasound but also to miss some cancers. As the stiffness of a lesion is found to be influenced by individual patient characteristics, incorporation of lesion stiffness in more individualized assessments may be key to the problem of reducing unnecessary breast biopsies without impairing the breast cancer detection rate. Thus, in this study, we evaluated whether an intelligent algorithm incorporating traditional SWE values as well as other patient and clinical variables (hereafter “intelligent SWE”) could reduce the number of unnecessary breast biopsies without impairing the breast cancer detection rate compared to traditional SWE and B-mode breast ultrasound for patients with suspicious breast lesions. Methods: We trained, tested, and validated machine learning algorithms using patient, clinical, ultrasound, and SWE information to classify breast masses. We used international, multicenter data from 857 women with BI-RADS 4 breast masses at 12 study sites in 7 countries. Patients underwent B-mode breast ultrasound, SWE, and subsequent histopathologic evaluation. 10-fold cross-validation was used to train and test the algorithms on data from 11 of the 12 sites which were further validated using the additional site’s data. The results of B-mode breast ultrasound, traditional SWE, and intelligent SWE were compared to the gold standard of histopathologic evaluation. We calculated sensitivity, specificity, and AUROC and used McNemar tests to test for significant differences in diagnostic performance. Results: The mean age was 49.5 years (SD 16.3) and 42.2% breast masses (n=362 of 857) were found to be malignant as confirmed by histopathology. In the external validation set (n=285), traditional SWE showed a significantly higher diagnostic performance compared to B-mode breast ultrasound (P < 0.001), whereas intelligent SWE outperformed both B-mode breast ultrasound and traditional SWE (P < 0.001). The neural network algorithm showed a significantly higher diagnostic performance compared to the Logistic Regression with Elastic Net Penalty (P = 0.004). The neural network algorithm achieved a sensitivity of 100% (95% CI 97.1 to 100%, 126 of 126) and a specificity of 50.3% (95% CI 42.3 to 58.3%, 80 of 159); the number of unnecessary biopsies were reduced by 50.3% (79 vs. 159) without missing any cancer compared to B-mode breast ultrasound. Model-agnostic variable importance plots to provide insights into the model predictions showed that the three most important variables for intelligent SWE were patient age followed by Shear-Wave velocity and orientation of the lesion (parallel vs. not parallel) in B-mode ultrasound. Conclusion: This is the first evidence which suggests that the majority of false-positive breast biopsies could be safely avoided by using intelligent SWE without impairing breast cancer detection rates. These results may be helpful in their ability to reduce treatment burden for patients, providers, and healthcare systems. Trial registration: NCT02638935. Funding: Siemens Medical Solutions USA, Inc
Diagnostic Performance ComparisonB-mode Breast UltrasoundTraditional Shear-Wave ElastographyIntelligent Shear-Wave Elastography – Logistic Regression with Elastic Net PenaltyIntelligent Shear-Wave Elastography – neural networkAUROC – value (95% CI)–0.84 (0.79-0.89)0.93 (0.90-0.95)0.93 (0.90-0.96)Sensitivity – % (95% CI); no.100% (97.1-100%); 126 of 12697.6% (93.2-99.5%); 123 of 126100% (97.1-100%); 126 of 126100% (97.1-100%); 126 of 126Specificity – % (95% CI); no.0% (0.0-2.3%); 0 of 15923.9% (17.5-31.3%); 38 of 15936.5% (29.0-44.5%); 58 of 15950.3% (42.3-58.3%); 80 of 159Negative predictive value – % (95% CI); no.–92.7% (80.1-98.5%); 38 of 41100% (93.8-100%); 58 of 58100% (95.5-100%); 80 of 80Positive predictive value – % (95% CI); no.44.2% (38.4-50.2); 126 of 28550.4% (44.0-56.8%); 123 of 24455.5% (48.8-62.1%); 126 of 22761.5% (54.4-68.2%); 126 of 205
Citation Format: André Pfob, Chris Sidey-Gibbons, Richard G. Barr, Volker Duda, Zaher Alwafai, Corinne Balleyguier, Dirk-André Clevert, Sarah Fastner, Christina Gomez, Manuela Goncalo, Ines Gruber, Markus Hahn, André Hennigs, Chi Ho, Panagiotis Kapetas, Sheng-Chieh Lu, Juliane Nees, Ralf Ohlinger, Fabian Riedel, Matthieu Rutten, Benedikt Schaefgen, Anne Stieber, Riku Togawa, Mitsuhiro Tozaki, Sebastian Wojcinski, Cai Xu, Geraldine Rauch, Joerg Heil, Michael Golatta. Intelligent shear-wave elastography to reduce unnecessary biopsies in breast cancer diagnosis (INSPiRED 002): An international, multicenter analysis abstract. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD11-05.
Abstract
Background: Anti-PD(L)1 in addition to neoadjuvant chemotherapy (NAC) can achieve pathologic complete response (pCR) rates of up to 65% in patients with early stage triple negative breast ...cancer (TNBC). However, patients with non-pCR can have dismal prognosis. Innovative strategies that render the tumor microenvironment more sensitive to anti-PD(L)1 may confer benefit. Preclinical studies have shown that hypofractionated radiation therapy (RT) delivered to an in-situ breast tumor, when combined with immune checkpoint blockade, stimulates anti-tumor immune responses and induces long-term, tumor-specific memory. Here, we report the first results of a phase II study that established the feasibility and efficacy of this approach in the pre-operative treatment setting for TNBC. Methods: Fifty patients with stage I-III TNBC, defined as ER<10%,PR<10%, HER2-negative, were enrolled between 12/17-4/21. Study treatment consisted of one cycle (C1) of pembro (200 mg iv q 3wks), followed by cycle 2 (C2) of pembro + RT (24Gy) delivered to a breast primary, followed by NAC regimen per MD choice, surgery and adjuvant therapy. Paired tumor biopsies and blood were collected at 3 serial time points: 1) baseline (pre-treatment); 2) after pembro C1; 3) after pembro C2 + RT (prior to initiation of NAC). All patients received breast and axillary surgery and postoperative RT to the chest wall and regional lymph nodes. Dual primary endpoints were: 1) feasibility, defined by the number of patients who did not necessitate a >4-week delay in initiating NAC after pembro C2 + RT; 2) change in tumor infiltrating lymphocyte (TIL) score. Secondary endpoints included pCR, defined as ypT0/TisypN0, in addition to toxicity and cosmesis evaluations. Results: To date, 50 patients are evaluable with a median follow up of 12 months (range 6-12). Median age of cohort is 55y (range 26-76). The majority (92%) were clinical stage II; 2% stage I and 6% stage III. 34% of the cohort had biopsy-proven, node positive disease. All patients received a taxane, 52% carboplatin and 74% anthracycline. 12% did not complete the planned course of NAC due to toxicities. No patients experienced a delay in initiating NAC. 50% received breast-conserving surgery and 50% mastectomy. Grade 1 or 2 toxicities consisted of fatigue (76%), nausea (66%), maculopapular rash (32%), diarrhea (38%), colitis (2%), hypothyroidism (8%) and peripheral neuropathy (40%). Four patients had grade 3 toxicities that were attributable to pembro: hyponatremia(1), colitis (1), adrenal insufficiency(1) and pneumonitis (1). Three patients had grade 4 neutropenia which were not attributable to pembro. The overall rate of pCR was 74% (37/50). Among the 13 patients with non-pCR, 0% were RCB 1, 16% RCB 2 and 10% RCB 3. Among the 17 N+ patients, 13 converted to ypN0, 1 ypN1mic and 3 ypN1a. No patients progressed during treatment. Changes in TIL count, PD-L1 and other biomarkers after pembro +/- RT and their association with treatment response, will be presented at the meeting. Conclusions: The novel combination of pre-operative pembro followed by the addition of RT to pembro prior to NAC is not only feasible, but also achieves pCR rates that are higher-than-expected compared to the pembro arm of KEYNOTE-522. AEs were consistent with known safety profiles of each agent. If confirmed by larger, randomized studies, this combination will be paradigm-changing for the treatment of TNBC.
Citation Format: Heather L McArthur, Stephen Shiao, Scott Karlan, Reva Basho, Farin Amersi, Michele Burnison, Amin Mirhadi, Alice Chung, Cathie T Chung, Catherine Dang, Heather Richardson, Armando E Giuliano, Nimmi Kapoor, Brigid Larkin, Hector Godinez, Samantha A Dunn, Negin Habibi Khameneh, Simon Knott, Philomena McAndrew, Monica Mita, Dorothy J Park, Christina Abaya, Jonathan H Chen, Amy Ly, Veerle Bossuyt, Alice Ho. The PEARL trial: Pre-operative pembrolizumab with radiation therapy in early stage triple negative breast cancer abstract. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD10-01.
Summary
Hypoxia and HIF1α signaling direct tissue‐specific gene responses regulating tumor progression, invasion, and metastasis. By integrating HIF1α knockdown and hypoxia‐induced gene expression ...changes, this study identifies a melanocyte‐specific, HIF1α‐dependent/hypoxia‐responsive gene expression signature. Integration of these gene expression changes with HIF1α ChIP‐Seq analysis identifies 81 HIF1α direct target genes in melanocytes. The expression levels for 10 of the HIF1α direct targets – GAPDH, PKM, PPAT, DARS, DTWD1, SEH1L, ZNF292, RLF, AGTRAP, and GPC6 – are significantly correlated with reduced time of disease‐free status in melanoma by logistic regression (P‐value = 0.0013) and ROC curve analysis (AUC = 0.826, P‐value < 0.0001). This HIF1α‐regulated profile defines a melanocyte‐specific response under hypoxia, and demonstrates the role of HIF1α as an invasive cell state gatekeeper in regulating cellular metabolism, chromatin and transcriptional regulation, vascularization, and invasion.
Intrauterine devices (IUDs), long‐acting and reversible contraceptives, induce a number of immunological and biochemical changes in the uterine environment that could affect endometrial cancer (EC) ...risk. We addressed this relationship through a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We combined individual‐level data from 4 cohort and 14 case‐control studies, in total 8,801 EC cases and 15,357 controls. Using multivariable logistic regression, we estimated pooled odds ratios (pooled‐ORs) and 95% confidence intervals (CIs) for EC risk associated with ever use, type of device, ages at first and last use, duration of use and time since last use, stratified by study and adjusted for confounders. Ever use of IUDs was inversely related to EC risk (pooled‐OR = 0.81, 95% CI = 0.74–0.90). Compared with never use, reduced risk of EC was observed for inert IUDs (pooled‐OR = 0.69, 95% CI = 0.58–0.82), older age at first use (≥35 years pooled‐OR = 0.53, 95% CI = 0.43–0.67), older age at last use (≥45 years pooled‐OR = 0.60, 95% CI = 0.50–0.72), longer duration of use (≥10 years pooled‐OR = 0.61, 95% CI = 0.52–0.71) and recent use (within 1 year of study entry pooled‐OR = 0.39, 95% CI = 0.30–0.49). Future studies are needed to assess the respective roles of detection biases and biologic effects related to foreign body responses in the endometrium, heavier bleeding (and increased clearance of carcinogenic cells) and localized hormonal changes.
What's new?
Are IUDs associated with endometrial cancer? Around the world, the intrauterine device is gaining popularity as a long‐term birth control strategy. Positioned as it is embedded in the uterine lining, an IUD could affect endometrial tissue. This study builds on previous work by considering the type of device used, in addition to factors such as duration of use. The authors found that women who had used an IUD, particularly an inert IUD, had less risk of endometrial cancer. The longer the device was used, they found, the more the cancer risk decreased.
Tricho-hepato-enteric syndrome (THE-S) is characterized by severe infantile diarrhea, failure to thrive, dysmorphism, woolly hair, and immune or hepatic dysfunction. We report two cases of East Asian ...descent with THE-S who had remained undiagnosed despite extensive investigations but were diagnosed on whole exome sequencing (WES). Both cases presented with chronic diarrhea, failure to thrive, and recurrent infections. Case 1 had posteriorly rotated low set ears, mild retrognathia, and fine curly hypopigmented hair. She was managed with prolonged total parenteral nutrition and intravenous immunoglobulin infusions. Case 2 had sparse coarse brown hair as well as multiple lentigines and café-au-lait macules. She was managed with amino acid-based formula. For both cases, routine investigations were inconclusive. WES in both cases showed biallelic truncating mutations in
TTC37
(c.3507T>G;p.Y1169X and c.3601C>T;p.R1201X in case 1 and c.3507T>G;p.Y1169X and c.154G>T;p.E52X in case 2), suggesting a diagnosis of THE-S.
Conclusion
: We present novel mutations in the
TTC37
gene in two individuals of East Asian descent with the rare THE-S, detected by WES. Future identification of patients with THE-S and establishing genotype-phenotype correlations will aid in counseling the patients and their families.
What is Known:
•
Tricho-Hepato-Enteric syndrome
(
THE-S
)
is characterized by severe infantile diarrhea
,
failure to thrive
,
dysmorphism
,
woolly hair
,
and immune or hepatic dysfunction
.
•
Complex patients with diagnostic dilemmas undergo extensive investigations
.
What is New:
•
This is a report of novel mutations in TTC37 in individuals of East Asian descent
.
•
Whole exome sequencing (WES) can be useful in certain complex cases with diagnostic dilemmas
.
Identification of drug targets and mechanism of action (MoA) for new and uncharacterized anticancer drugs is important for optimization of treatment efficacy. Current MoA prediction largely relies on ...prior information including side effects, therapeutic indication, and chemoinformatics. Such information is not transferable or applicable for newly identified, previously uncharacterized small molecules. Therefore, a shift in the paradigm of MoA predictions is necessary toward development of unbiased approaches that can elucidate drug relationships and efficiently classify new compounds with basic input data. We propose here a new integrative computational pharmacogenomic approach, referred to as Drug Network Fusion (DNF), to infer scalable drug taxonomies that rely only on basic drug characteristics toward elucidating drug-drug relationships. DNF is the first framework to integrate drug structural information, high-throughput drug perturbation, and drug sensitivity profiles, enabling drug classification of new experimental compounds with minimal prior information. DNF taxonomy succeeded in identifying pertinent and novel drug-drug relationships, making it suitable for investigating experimental drugs with potential new targets or MoA. The scalability of DNF facilitated identification of key drug relationships across different drug categories, providing a flexible tool for potential clinical applications in precision medicine. Our results support DNF as a valuable resource to the cancer research community by providing new hypotheses on compound MoA and potential insights for drug repurposing.
.
Next-generation sequencing of antibody transcripts from HIV-1-infected individuals with broadly neutralizing antibodies could provide an efficient means for identifying somatic variants and ...characterizing their lineages. Here, we used 454 pyrosequencing and identity/divergence grid sampling to analyze heavy- and lightchain sequences from donor N152, the source of the broadly neutralizing antibody 10E8. We identified variants with up to 28% difference in amino acid sequence. Heavy-and light-chain phylogenetic trees of identified 10E8 variants displayed similar architectures, and 10E8 variants reconstituted from matched and unmatched phylogenetic branches displayed significantly lower autoreactivity when matched. To test the generality of phylogenetic pairing, we analyzed donor International AIDS Vaccine Initiative 84, the source of antibodies PGT141-145. Heavy-and light-chain phylogenetic trees of PGT141-145 somatic variants also displayed remarkably similar architectures; in this case, branch pairings could be anchored by known PGT141-145 antibodies. Altogether, our findings suggest that phylogenetic matching of heavy and light chains can provide a means to approximate natural pairings.
Abstract only Introduction: Congenitally corrected transposition of the great arteries (ccTGA) is rare with varied associated cardiac defects and rhythm abnormalities. We aimed to describe the ...natural history, associated anomalies and prenatal outcome in a cohort of prenatally diagnosed patients in which biventricular repair is anticipated. Methods: A retrospective cohort study was conducted via the Fetal Heart Society Research Collaborative. All fetuses with ccTGA encountered at 15 North American cardiac centers between 1/2004-7/2020 were identified. Fetuses with a hypoplastic ventricle precluding biventricular repair were excluded. Data is presented as median (interquartile range). Results: Inclusion criteria were met in 139 fetuses who were diagnosed with ccTGA at 24 (21-29) weeks. There was a family history of congenital heart disease in 12%. Maternal diabetes was present in 10%. Prenatal genetic testing in 50 pregnancies was normal. Excluding 14 fetuses with heterotaxy, extracardiac anomalies were observed in 9/125 (7.1%). Associated cardiac/extracardiac defects are detailed in table 1. Fetal atrioventricular block (AVB) was present in 17 fetuses (12%), diagnosed at a median of 26 (23-28), range 20-36 weeks. Two fetuses had SVT; 1 self-resolved and 1 during labor. Change occurred during follow-up in 34 fetuses, most commonly in severity of tricuspid regurgitation (6 improved, 4 worsened) and worsening of pulmonary stenosis (n=5). There were 112 live births, 17 terminations, 2 fetal deaths (FD) and 8 lost to follow-up. Both fetuses with FD had AVB, making the intrauterine mortality associated with fetal AVB 11.8% (2/17). Conclusions: This study represents the largest cohort to date of fetuses with ccTGA. Fetal ccTGA is associated with a spectrum of cardiac defects that may evolve, with extracardiac pathology occurring in 7.1%. AVB is found in 12% of fetuses and is a risk factor for FD. This data informs fetal counseling and can aid in delivery planning and perinatal care.
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