Are There Disparities in Breast Reconstruction After Contralateral Prophylactic Mastectomy?

INTRODUCTION: Despite national guidelines against contralateral prophylactic mastectomy (CPM) in low- to moderate-risk breast cancer, CPM use continues to rise. Breast reconstruction improves health-related quality of life and satisfaction among women undergoing mastectomy. Given the lack of data regarding factors associated with reconstruction after CPM and the known benefits of reconstruction, we sought to investigate whether disparities exist in receipt of reconstruction after CPM. METHODS: The 2004-2017 National Cancer Database was queried to identify women diagnosed with breast cancer who underwent unilateral mastectomy with CPM. Patients were divided into two groups: those who underwent planned reconstruction at any timepoint and those who did not. A secondary analysis comparing types of reconstruction (tissue, implant, combined) was conducted. Patient, tumor, and demographic characteristics were analyzed using chi-square test and odds ratios were calculated using generalized estimating equations. RESULTS: The cohort included 1,73,249 women: 95,818 (55.3%) underwent reconstruction and 77,431 (45.7%) did not. Both the rate CPM and the proportion of women undergoing reconstruction after CPM increased between 2004 and 2017. Of the women who had reconstruction, 40,840 (51.7%) received implants, 29,807 (37.7%) had tissue, and 8352 (10.6%) had combined reconstruction. After adjusted analysis, factors associated with reconstruction were young age, Hispanic ethnicity, private insurance, and living in an area with the highest education and median income (P < 0.01). Patients who underwent reconstruction were less likely to have radiation (P < 0.01) and chemotherapy (P < 0.01), more likely to have stage I disease (P < 0.01), and to be treated at an integrated cancer center (P < 0.01). CONCLUSIONS: Reconstruction after CPM is disproportionately received by younger women, Hispanics, those with private insurance, and higher socioeconomic status and education. While the rate of reconstruction after CPM is increasing, there remain significant disparities. Conscious efforts must be made to eliminate these disparities, especially given the known benefits of reconstruction after mastectomy.

DNA methylation profiling in Kabuki syndrome: reclassification of germline KMT2D VUS and sensitivity in validating postzygotic mosaicism.

Autosomal dominant Kabuki syndrome (KS) is a rare multiple congenital anomalies/neurodevelopmental disorder caused by heterozygous inactivating variants or structural rearrangements of the lysine-specific methyltransferase 2D (KMT2D) gene. While it is often recognizable due to a distinctive gestalt, the disorder is clinically variable, and a phenotypic scoring system has been introduced to help clinicians to reach a clinical diagnosis. The phenotype, however, can be less pronounced in some patients, including those carrying postzygotic mutations. The full spectrum of pathogenic variation in KMT2D has not fully been characterized, which may hamper the clinical classification of a portion of these variants. DNA methylation (DNAm) profiling has successfully been used as a tool to classify variants in genes associated with several neurodevelopmental disorders, including KS. In this work, we applied a KS-specific DNAm signature in a cohort of 13 individuals with KMT2D VUS and clinical features suggestive or overlapping with KS. We succeeded in correctly classifying all the tested individuals, confirming diagnosis for three subjects and rejecting the pathogenic role of 10 VUS in the context of KS. In the latter group, exome sequencing allowed to identify the genetic cause underlying the disorder in three subjects. By testing five individuals with postzygotic pathogenic KMT2D variants, we also provide evidence that DNAm profiling has power to recognize pathogenic variants at different levels of mosaicism, identifying 15% as the minimum threshold for which DNAm profiling can be applied as an informative diagnostic tool in KS mosaics.

Matrisome and Immune Pathways Contribute to Extreme Vascular Outcomes in Williams-Beuren Syndrome.

BACKGROUND: Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). Its severity varies: ~20% of people with Williams-Beuren syndrome have SVAS requiring surgical intervention, whereas ~35% have no appreciable SVAS. The remaining individuals have SVAS of intermediate severity. Little is known about genetic modifiers that contribute to this variability. METHODS AND RESULTS: We performed genome sequencing on 473 individuals with Williams-Beuren syndrome and developed strategies for modifier discovery in this rare disease population. Approaches include extreme phenotyping and nonsynonymous variant prioritization, followed by gene set enrichment and pathway-level association tests. We next used GTEx v8 and proteomic data sets to verify expression of candidate modifiers in relevant tissues. Finally, we evaluated overlap between the genes/pathways identified here and those ascertained through larger aortic disease/trait genome-wide association studies. We show that SVAS severity in Williams-Beuren syndrome is associated with increased frequency of common and rarer variants in matrisome and immune pathways. Two implicated matrisome genes (ACAN and LTBP4) were uniquely expressed in the aorta. Many genes in the identified pathways were previously reported in genome-wide association studies for aneurysm, bicuspid aortic valve, or aortic size. CONCLUSIONS: Smaller sample sizes in rare disease studies necessitate new approaches to detect modifiers. Our strategies identified variation in matrisome and immune pathways that are associated with SVAS severity. These findings suggest that, like other aortopathies, SVAS may be influenced by the balance of synthesis and degradation of matrisome proteins. Leveraging multiomic data and results from larger aorta-focused genome-wide association studies may accelerate modifier discovery for rare aortopathies like SVAS.

FOXI3 pathogenic variants cause one form of craniofacial microsomia.

Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown. A total of 670 patients belonging to unrelated pedigrees with European and Chinese ancestry with CFM, are investigated. We identify 18 likely pathogenic variants in 21 probands (3.1%) in FOXI3. Biochemical experiments on transcriptional activity and subcellular localization of the likely pathogenic FOXI3 variants, and knock-in mouse studies strongly support the involvement of FOXI3 in CFM. Our findings indicate autosomal dominant inheritance with reduced penetrance, and/or autosomal recessive inheritance. The phenotypic expression of the FOXI3 variants is variable. The penetrance of the likely pathogenic variants in the seemingly dominant form is reduced, since a considerable number of such variants in affected individuals were inherited from non-affected parents. Here we provide suggestive evidence that common variation in the FOXI3 allele in trans with the pathogenic variant could modify the phenotypic severity and accounts for the incomplete penetrance.

Factors Associated With Cosmetic Outcomes After Treatment With a Novel Form of Breast Intraoperative Radiation Therapy.

INTRODUCTION: Precision breast intraoperative radiation therapy (PB-IORT) incorporates computed tomography-guided treatment planning and high dose rate brachytherapy to deliver a single dose of highly conformal radiational therapy. The purpose of this study is to determine factors associated with poor cosmetic outcomes after treatment with PB-IORT. METHODS: The study included all consecutive participants enrolled in an ongoing phase II clinical trial that had completed a minimum of 12 mo of follow-up. A poor cosmetic outcome was defined as scoring "fair" or "poor" on the Harvard Cosmesis evaluation, or "some" or "very much" on any of the three general cosmesis categories. Statistical analysis was performed utilizing R. RESULTS: The final cohort included 201 participants, of which 181 (90%) had an overall good/excellent cosmetic outcome. Group 1 consisted of 162 (81%) participants who reported only excellent/good cosmetic outcomes. Group 2 consisted of 39 (19%) participants who reported some aspect of a poor cosmetic outcome. On multivariable analysis, participants with ductal carcinoma in situ were significantly more likely to experience a poor cosmetic outcome (odds ratio 2.45, 95% confidence interval 1.03-5.82, P = 0.04), and those who received subsequent whole breast irradiation were also more likely to have a poor cosmetic outcome (odds ratio 10.20, 95% confidence interval CI 1.04-99.95, P = 0.04). CONCLUSIONS: Patients with need for further radiation after PB-IORT are at increased risk for a poor cosmetic outcome. Larger balloon volume and distance between the skin do not have deleterious effects on cosmetic outcomes.

Impact of a High-Resolution Anoscopy Clinic on Management of Anal Dysplasia in Women Living With HIV.

BACKGROUND: The rate of anal squamous cell cancer (aSCC) is increasing among women living with HIV. Treatment of precursor high grade squamous intraepithelial lesions (HSIL) may reduce the risk of progression to aSCC. The objective of this study was to examine effects of a dedicated high-resolution anoscopy (HRA) clinic on management of HSIL in women with HIV. METHODS: Women living with HIV who underwent anal dysplasia screening at a single institution between 2006 and 2020 were reviewed. Those who underwent screening before (Group A) and after (Group B) the implementation of an HRA program in 2017 were compared. The primary outcome of interest was the successful detection and treatment of HSIL. RESULTS: A total of 201 women living with HIV underwent anal dysplasia screening between 2006 and 2020. Seventy-seven patients were found to have abnormal anal cytology requiring further treatment: 43 (55.8%) in Group A and 34 (44.2%) patients in Group B. Of the patients with abnormal anal cytology, 76.7% of patients in Group A received further biopsy and treatment, whereas 79.4% of Group B patients underwent subsequent biopsy and treatment. In propensity score weighting logistic regression analysis, the Group B was 4.6 times as likely to diagnosis HSIL on biopsy compared to Group A (OR = 4.60, 95% CI: 1.15 to 18.38, P = .03). CONCLUSIONS: Anal dysplasia is common among women living with HIV. The establishment of a HRA program was associated with increased identification and treatment of HSIL among women living with HIV, which may prevent the progression to aSCC.

Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders.

An expanding range of genetic syndromes are characterized by genome-wide disruptions in DNA methylation profiles referred to as episignatures. Episignatures are distinct, highly sensitive, and specific biomarkers that have recently been applied in clinical diagnosis of genetic syndromes. Episignatures are contained within the broader disorder-specific genome-wide DNA methylation changes, which can share significant overlap among different conditions. In this study, we performed functional genomic assessment and comparison of disorder-specific and overlapping genome-wide DNA methylation changes related to 65 genetic syndromes with previously described episignatures. We demonstrate evidence of disorder-specific and recurring genome-wide differentially methylated probes (DMPs) and regions (DMRs). The overall distribution of DMPs and DMRs across the majority of the neurodevelopmental genetic syndromes analyzed showed substantial enrichment in gene promoters and CpG islands, and under-representation of the more variable intergenic regions. Analysis showed significant enrichment of the DMPs and DMRs in gene pathways and processes related to neurodevelopment, including neurogenesis, synaptic signaling and synaptic transmission. This study expands beyond the diagnostic utility of DNA methylation episignatures by demonstrating correlation between the function of the mutated genes and the consequent genomic DNA methylation profiles as a key functional element in the molecular etiology of genetic neurodevelopmental disorders.

Genome-wide DNA methylation profiling and exome sequencing resolved a long-time misdiagnosed case.

The search for aetiology of Mendelian disorders is traditionally based on the observation of clinical phenotypes and molecular screening of associated genes. However, a disease-specific diagnosis can be challenging. In this study we detail how the combinatorial genomic and epigenomic assessment allowed to find the underlying molecular event of a clinical case that remained misdiagnosed for years. The individual was referred as affected by an atypical form of Kabuki syndrome with a variant of uncertain significance in the KMT2D gene. However, significant inconsistencies with this diagnosis emerged upon familial segregation of the variant and after the clinical re-evaluation. Therefore, we applied an epigenomic strategy by studying the DNA methylation profile which resulted not consistent with the Kabuki syndrome episignature or with any other disorder-specific episignature described so far, providing strong evidence that the Kabuki syndrome diagnosis does not apply. This result led us to further investigate for epigenetic machinery diseases by using a multigene panel for chromatinopathies. Since this analysis yielded negative results, we applied a whole exome sequencing and identified a de novo pathogenic variant in the CTNNB1 gene associated to NEDSDV syndrome, a neurodevelopmental disorder characterized by intellectual disability and craniofacial anomalies. Based on molecular results and the updated clinical features, we confirmed the NEDSDV diagnosis. Our findings show that the combination of genomic and epigenomics strategies, along with a deeper analysis of clinical phenotype, may provide a significant improvement in the diagnostic protocols for rare genetic disorders and help resolve long-time misdiagnosed and unsolved case.

Residents as Leaders: Using a Delphi Process to Conduct an Institutional Preoperative Patient Optimization Quality Improvement Initiative.

BACKGROUND: Many residency programs struggle to meet the ACGME requirement for resident participation in quality improvement initiatives. STUDY DESIGN: As part of an institutional quality improvement effort, trainees from the Departments of Surgery and Anesthesiology at a single academic medical center were teamed with institutional content experts in 7 key risk factor areas within preoperative patient optimization. A systematic review of each subject matter area was performed using the MEDLINE database. Institutional recommendations for the screening and management of each risk factor were developed and approved using modified Delphi consensus methodology. Upon project completion, an electronic survey was administered to all individuals who participated in the process to assess the perceived value of participation. RESULTS: Fifty-one perioperative stakeholders participated in recommendation development: 26 trainees and 25 content experts. Residents led 6 out of 7 groups specific to a subject area within preoperative optimization. A total of 4,649 abstracts were identified, of which 456 full-text articles were selected for inclusion in recommendation development. Seventeen out of 26 (65.4%) trainees completed the survey. The vast majority of trainees reported increased understanding of their preoperative optimization subject area (15/17 [88.2%]) as well as the Delphi consensus method (14/17 [82.4%]) after participation in the project. Fourteen out of 17 (82.4%) trainees stated that they would participate in a similar quality improvement initiative again. CONCLUSIONS: We demonstrate a novel way to involve trainees in an institutional quality initiative that served to educate trainees in quality improvement, the systematic review process, Delphi methodology, and preoperative optimization. This study provides a framework that other residency programs can use to engage residents in institutional quality improvement efforts.

A comparative study using time-driven activity-based costing in single-fraction breast high-dose rate brachytherapy: An integrated brachytherapy suite vs. decentralized workflow.

INTRODUCTION: Precision breast intraoperative radiation therapy (PB-IORT) is a novel approach to adjuvant radiation therapy for early-stage breast cancer performed as part of a phase II clinical trial at two institutions. One institution performs the entire procedure in an integrated brachytherapy suite which contains a CT-on-rails imaging unit and full anesthesia capabilities. At the other, breast conserving surgery and radiation therapy take place in two separate locations. Here, we utilize time-driven activity-based costing (TDABC) to compare these two models for the delivery of PB-IORT. METHODS: Process maps were created to describe each step required to deliver PB-IORT at each institution, including personnel, equipment, and supplies. Time investment was estimated for each step. The capacity cost rate was determined for each resource, and total costs of care were then calculated by multiplying the capacity cost rates by the time estimate for the process step and adding any additional product costs. RESULTS: PB-IORT costs less to deliver at a distributed facility, as is more commonly available, than an integrated brachytherapy suite ($3,262.22 vs. $3,996.01). The largest source of costs in both settings ($2,400) was consumable supplies, including the brachytherapy balloon applicator. The difference in costs for the two facility types was driven by personnel costs ($1,263.41 vs. $764.89). In the integrated facility, increased time required by radiation oncology nursing and the anesthesia attending translated to the greatest increases in cost. Equipment costs were also slightly higher in the integrated suite setting ($332.60 vs. $97.33). CONCLUSIONS: The overall cost of care is higher when utilizing an integrated brachytherapy suite to deliver PB-IORT. This was primarily driven by additional personnel costs from nursing and anesthesia, although the greatest cost of delivery in both settings was the disposable brachytherapy applicator. These differences in cost must be balanced against the potential impact on patient experience with these approaches.

Effects of a novel form of intraoperative radiation therapy on quality of life among patients with early-stage breast cancer.

PURPOSE: To investigate patient-perceived quality of life (QOL) among patients treated with a novel form of breast intraoperative radiation therapy (PB-IORT). METHODS AND MATERIALS: Patients treated with PB-IORT as part of a phase II clinical trial from 2013 to 2020 were identified. Patients were given the European Organization for Research and Treatment of Cancer (EORTC) core 30-item Quality of Life Questionnaire (QLQ-C30) encompassing global health, functionality, and symptomatology at baseline, 1-month, 6-months, 12-months, and 24-months after PB-IORT. Scores were on a 100-point scale with change greater than 10 considered clinically significant. Scores at interval follow-up were compared to baseline using repeated measure modeling with an unstructured covariance matrix. RESULTS: The cohort consisted of 303 patients, a majority of which were White (84.2%) with a median age of 64 years (IQR: 52, 76). One month after PB-IORT, a decline from baseline in physical (-2.5, 95% CI: -4.4 - -0.55, p = 0.01), role (-7.6, 95% CI: -11.7 - -3.5, p < 0.001), and social functioning (-3.0, 95% CI: -5.5 - -0.42, p = 0.02) were observed, which correlated with increased fatigue (8.4, 95% CI: 5.5-11.3, p < 0.001). At 6 months, nearly all QOL measures returned to baseline or improved. There were no statistically or clinically significant differences from baseline in overall global health. All functional and symptom scale differences were less than 10, indicating minimal clinical significance. CONCLUSIONS: PB-IORT has minimal negative impact on QOL, further supporting this patient-centered treatment approach for early-stage breast cancer.

Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders.

Overlapping clinical phenotypes and an expanding breadth and complexity of genomic associations are a growing challenge in the diagnosis and clinical management of Mendelian disorders. The functional consequences and clinical impacts of genomic variation may involve unique, disorder-specific, genomic DNA methylation episignatures. In this study, we describe 19 novel episignature disorders and compare the findings alongside 38 previously established episignatures for a total of 57 episignatures associated with 65 genetic syndromes. We demonstrate increasing resolution and specificity ranging from protein complex, gene, sub-gene, protein domain, and even single nucleotide-level Mendelian episignatures. We show the power of multiclass modeling to develop highly accurate and disease-specific diagnostic classifiers. This study significantly expands the number and spectrum of disorders with detectable DNA methylation episignatures, improves the clinical diagnostic capabilities through the resolution of unsolved cases and the reclassification of variants of unknown clinical significance, and provides further insight into the molecular etiology of Mendelian conditions.

DNA methylation episignature testing improves molecular diagnosis of Mendelian chromatinopathies.

PURPOSE: Chromatinopathies include more than 50 disorders caused by disease-causing variants of various components of chromatin structure and function. Many of these disorders exhibit unique genome-wide DNA methylation profiles, known as episignatures. In this study, the methylation profile of a large cohort of individuals with chromatinopathies was analyzed for episignature detection. METHODS: DNA methylation data was generated on extracted blood samples from 129 affected individuals with the Illumina Infinium EPIC arrays and analyzed using an established bioinformatic pipeline. RESULTS: The DNA methylation profiles matched and confirmed the sequence findings in both the discovery and validation cohorts. Twenty-five affected individuals carrying a variant of uncertain significance, did not show a methylation profile matching any of the known episignatures. Three additional variant of uncertain significance cases with an identified KDM6A variant were re-classified as likely pathogenic (n = 2) or re-assigned as Wolf-Hirschhorn syndrome (n = 1). Thirty of the 33 Next Generation Sequencing negative cases did not match a defined episignature while three matched Kabuki syndrome, Rubinstein-Taybi syndrome and BAFopathy respectively. CONCLUSION: With the expanding clinical utility of the EpiSign assay, DNA methylation analysis should be considered part of the testing cascade for individuals presenting with clinical features of Mendelian chromatinopathy disorders.

Clinical heterogeneity of Kabuki syndrome in a cohort of Italian patients and review of the literature.

Kabuki syndrome (KS) is a well-recognized disorder characterized by postnatal growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability. The syndrome is caused by KMT2D gene mutations or less frequently KDM6A gene mutations or deletions. We report a systematic evaluation of KS patients from Campania region of Italy; data were also compared with literature ones. We collected data of 15 subjects (8 males and 7 females with age range 10-26 years; mean age 16.9 years) with confirmed diagnosis of KS, representing the entire cohort of patients from Campania Region. Each patient performed biochemical testing and instrumental investigation. Neuro-intellectual development, cranio-facial dysmorphisms, and multisystem involvement data were collected retrospectively. For each category, type of defects and frequency of the anomalies were analyzed. Our observation shows that KS patients from Campania region have some particular and previously underscored, neurological and immunological findings. We found high prevalence of EEG's abnormalities (43%) and MRI brain abnormalities (60%). Microcephaly resulted more common in our series (33%), if compared with major cohorts described in literature. Biochemical features of immunodeficiency and autoimmune diseases including thyroid autoimmunity, polyserositis, and vitiligo were observed with high prevalence (54.5%). Low immunoglobulins levels were a frequent finding. Lymphocyte class investigation showed significantly reduced CD8 levels in one patient.Conclusions: These data confirm great heterogeneity of clinical manifestations in KS and suggest to introduce further clinical diagnostic criteria in order to perform a correct and precocious diagnosis. What is Known • Kabuki syndrome is characterized by growth deficiency, dysmorphic facial features, skeletal anomalies, and intellectual disability • Immune dysfunction is a common finding but autoimmune diseases are rarely seen • Neurological features are common What is New • Some particular facial features could help gestalt diagnosis (hypertelorism, broad nasal bridge, micrognathia, tooth agenesis, cutaneous haemangiomas and strabismus) • Higher prevalence of autoimmune disorders than previously reported • Particular neurological features are present in this cohort (EEG and MRI brain abnormalities).

A pilot trial of vaccination with Carcinoembryonic antigen and Her2/neu peptides in advanced colorectal cancer.

Checkpoint-blockade therapy (CBT) is approved for select colorectal cancer (CRC) patents, but additional immunotherapeutic options are needed. We hypothesized that vaccination with carcinoembryonic antigen (CEA) and Her2/neu (Her2) peptides would be immunogenic and well tolerated by participants with advanced CRC. A pilot clinical trial (NCT00091286) was conducted in HLA-A2+ or -A3+ Stage IIIC-IV CRC patients. Participants were vaccinated weekly with CEA and Her2 peptides plus tetanus peptide and GM-CSF emulsified in Montanide ISA-51 adjuvant for 3 weeks. Adverse events (AEs) were recorded per NIH Common Terminology Criteria for Adverse Events version 3. Immunogenicity was evaluated by interferon-gamma ELISpot assay of in vitro sensitized peripheral blood mononuclear cells and lymphocytes from the sentinel immunized node. Eleven participants were enrolled and treated; one was retrospectively found to be ineligible due to HLA type. All 11 participants were included in AEs and survival analyses, and the 10 eligible participants were evaluated for immunogenicity. All participants reported AEs: 82% were Grade 1-2, most commonly fatigue or injection site reactions. Two participants (18%) experienced treatment-related dose-limiting Grade 3 AEs; both were self-limiting. Immune responses to Her2 or CEA peptides were detected in 70% of participants. Median overall survival (OS) was 16 months; among those enrolled with no evidence of disease (n = 3), median OS was not reached after 10 years of follow-up. These data demonstrate that vaccination with CEA or Her2 peptides is well tolerated and immunogenic. Further study is warranted to assess potential clinical benefits of vaccination in advanced CRC either alone or in combination with CBT.

Identification of a DNA Methylation Episignature in the 22q11.2 Deletion Syndrome.

The 22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder in humans and is the result of a recurrent 1.5 to 2.5 Mb deletion, encompassing approximately 20-40 genes, respectively. The clinical presentation of the typical deletion includes: Velocardiofacial, Di George, Opitz G/BBB and Conotruncalanomaly face syndromes. Atypical deletions (proximal, distal or nested) are rare and characterized mainly by normal phenotype or mild intellectual disability and variable clinical features. The pathogenetic mechanisms underlying this disorder are not completely understood. Because the 22q11.2 region harbours genes coding for transcriptional factors and chromatin remodelers, in this study, we performed analysis of genome-wide DNA methylation of peripheral blood from 49 patients with 22q11.2DS using the Illumina Infinium Methylation EPIC bead chip arrays. This cohort comprises 43 typical, 2 proximal and 4 distal deletions. We demonstrated the evidence of a unique and highly specific episignature in all typical and proximal 22q11.2DS. The sensitivity and specificity of this signature was further confirmed by comparing it to over 1500 patients with other neurodevelopmental disorders with known episignatures. Mapping the 22q11.2DS DNA methylation episignature provides both novel insights into the molecular pathogenesis of this disorder and an effective tool in the molecular diagnosis of 22q11.2DS.

Effects of Adjuvant Endocrine Therapy Adherence and Radiation on Recurrence and Survival Among Older Women with Early-Stage Breast Cancer.

BACKGROUND: The Cancer and Leukemia Group-B 9343 (CALGB 9343) trial demonstrated that women aged ≥ 70 years with early-stage breast cancer can safely omit radiation therapy (RT) and be treated with breast-conserving surgery (BCS) and adjuvant endocrine therapy (AET) alone. AET adherence is low, leaving an undertreated cohort who may be at increased risk of recurrence and death. We hypothesized that AET adherence and adjuvant treatment choice impact recurrence and survival among CALGB 9343 eligible women. PATIENTS AND METHODS: SEER-Medicare was used to identify CALGB 9343 eligible women who underwent BCS between 2007 and 2016. Medicare claims were used to identify AET use, and the proportion of days covered by AET was used to categorize adherent (PDC ≥ 0.80) versus nonadherent patients (PDC < 0.80). Recurrence-free, cancer-specific, and overall survival were assessed using Cox proportional hazards models. RESULTS: In total, 10,719 women were identified, of whom 780 (7.3%) underwent BCS alone, 1490 (13.9%) underwent BCS + RT, 1663 (15.5%) underwent BCS + AET, and 6786 (63.3%) had BCS + RT + AET. Among women treated with BCS + AET, adherent patients had lower recurrence than did nonadherent patients (HR = 0.65, 95% CI: 0.50-0.85). With respect to adjuvant treatment combinations, there was no recurrence difference between the BCS + RT + AET group and BCS + AET group (HR = 0.81, 95% CI: 0.54-1.21). There was equivalent cancer-specific but worse overall survival in the BCS + AET group versus the BCS + AET + RT group. CONCLUSIONS: While BCS + RT + AET may represent overtreatment for some, AET nonadherent women who omit RT are at risk for worse outcomes. Treatment decisions regarding RT omission should be tailored to the individual patient, taking into consideration the chances of AET nonadherence and the patients' own risk tolerance.

Expanding the phenotype associated to KMT2A variants: overlapping clinical signs between Wiedemann-Steiner and Rubinstein-Taybi syndromes.

Lysine-specific methyltransferase 2A (KMT2A) is responsible for methylation of histone H3 (K4H3me) and contributes to chromatin remodeling, acting as "writer" of the epigenetic machinery. Mutations in KMT2A were first reported in Wiedemann-Steiner syndrome (WDSTS). More recently, KMT2A variants have been described in probands with a specific clinical diagnosis comprised in the so-called chromatinopathies. Such conditions, including WDSTS, are a group of overlapping disorders caused by mutations in genes coding for the epigenetic machinery. Among them, Rubinstein-Taybi syndrome (RSTS) is mainly caused by heterozygous pathogenic variants in CREBBP or EP300. In this work, we used next generation sequencing (either by custom-made panel or by whole exome) to identify alternative causative genes in individuals with a RSTS-like phenotype negative to CREBBP and EP300 mutational screening. In six patients we identified different novel unreported variants in KMT2A gene. The identified variants are de novo in at least four out of six tested individuals and all of them display some typical RSTS phenotypic features but also WDSTS specific signs. This study reinforces the concept that germline variants affecting the epigenetic machinery lead to a shared molecular effect (alteration of the chromatin state) determining superimposable clinical conditions.