Clinical implications of receptor conversions in breast cancer patients who have undergone neoadjuvant chemotherapy.

PURPOSE: In this study, we aimed to determine the incidence of receptor conversions after neoadjuvant chemotherapy (NAC) for breast cancer and assess the rate at which receptor conversion leads to changes in adjuvant therapy regimens. METHODS: We performed a retrospective review of female breast cancer patients treated with NAC at an academic breast center between January 2017 and October 2021. Patients with residual disease on surgical pathology and complete receptor status information for both pre-NAC and post-NAC specimens were included. Incidence of receptor conversions, defined as a change in at least one hormone receptor (HR) or HER2 status compared to preoperative specimens, was tabulated, and adjuvant therapy modalities were reviewed. Factors associated with receptor conversion were analyzed using chi-square tests and a binary logistic regression. RESULTS: Of the 240 patients with residual disease after NAC, 126 (52.5%) had receptor testing repeated. After NAC, 37 specimens (29%) had a receptor conversion. Receptor conversion resulted in the addition or removal of an adjuvant therapy in 8 patients (6%), indicating a number needed to screen of 16. Prior history of cancer, receipt of initial biopsy at an outside site, HR-positive tumors, and a pathologic stage of II or lower were factors associated with receptor conversions. CONCLUSION: HR and HER2 expression profiles frequently change after NAC and drive adjustments in adjuvant therapy regimens. Repeat testing of HR and HER2 expression should be considered in patients who receive NAC, especially in patients with early stage, HR-positive tumors whose initial biopsies were performed externally.

Neoadjuvant endocrine therapy expands stromal populations that predict poor prognosis in estrogen receptor-positive breast cancer.

The tumor microenvironment (TME) is an important modulator of response and resistance to endocrine therapy in estrogen receptor alpha (ER) positive breast cancer. Endocrine therapy is highly effective at reducing tumor burden and preventing recurrence in most estrogen receptor alpha (ER) positive breast cancers. Existing drugs work either directly by targeting tumor-cell ER or indirectly by inhibiting estrogen production in stromal cells with aromatase inhibitors (AI). However, many stromal cells also express ER and the direct impact of endocrine therapies on ER + stromal cells remain unclear. In this study, we investigated how neoadjuvant endocrine therapy (NET) directly effects stromal cells by measuring changes in stomal components of the TME that favor tumor progression. We previously defined two major subsets of tumor-associated stromal cells (TASCs): CD146 positive/CDCP1 negative (TASCCD146 ), CD146 negative/CDCP1 positive (TASCCDCP1 ), and generated a differentially expressed genes list associated with each type. Here, we applied the TASC gene list for classification and an algorithm that estimates immune cell abundance (TIMEx) to METABRIC transcriptomic data for ER + breast cancer patients coupled with multiplex imaging and analysis of paired tissue samples pre- and post- NET with the AI exemestane. TASCCDCP1 composition predicted for decreased patient survival in the METABRIC cohort. Exemestane treatment significantly increased expression of TASCCDCP1 and decreased expression of TASCCD146 . The posttreatment shift toward TASCCDCP1 composition correlated with increased macrophage infiltration and increased CD8+ T-cell, B cell, and general stromal components. The effectiveness of NET is currently based solely on the reduction of ER+ breast cancer cells. Here, we show NET displays clear TME effects that promote the expansion of the less favorable TASCCDCP1 population which are correlated with TME remodeling and reshaping immune infiltration supportive of tumor progression. Our findings highlight the need to further understand the role of endocrine therapy on TME remodeling, tumor progression, and patient outcomes.

Inhibition of BRAF and ERK1/2 has synergistic effects on thyroid cancer growth in vitro and in vivo.

Mutations in the BRAF gene are highly prevalent in thyroid cancer. However, the response rate of thyroid tumors to BRAF-directed therapies has been mixed. Increasingly, combination therapies inhibiting the MAPK pathway at multiple nodes have shown promise. Recently developed ERK1/2 inhibitors are of interest for use in combination therapies as they have the advantage of inhibiting the most downstream node of the MAPK pathway, therefore preventing pathway reactivation. Here, we examined the effect of combined BRAF inhibition (dabrafenib) and ERK1/2 inhibition (SCH772984) on the growth and survival of a panel of BRAF-mutant thyroid cancer cell lines using in vitro and in vivo approaches. We found that resistance due to MAPK pathway reactivation occurs quickly with single-agent BRAF inhibition, but can be prevented with combined BRAF and ERK1/2 inhibition. Combined inhibition also results in synergistic growth inhibition, decreased clonogenic survival, and enhanced induction of apoptosis in a subset of BRAF-mutant thyroid cancer cells. Finally, combined inhibition of BRAF and ERK1/2 results in enhanced inhibition of tumor growth in an anaplastic thyroid cancer in vivo model. These results provide key rationale to pursue combined BRAF and ERK1/2 inhibition as an alternative therapeutic strategy for BRAF-mutant advanced thyroid cancer patients.

A phase II clinical trial of the Aurora and angiogenic kinase inhibitor ENMD-2076 for previously treated, advanced, or metastatic triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) remains an aggressive breast cancer subtype with limited treatment options. ENMD-2076 is a small-molecule inhibitor of Aurora and angiogenic kinases with proapoptotic and antiproliferative activity in preclinical models of TNBC. METHODS: This dual-institution, single-arm, two-stage, phase II clinical trial enrolled patients with locally advanced or metastatic TNBC previously treated with one to three prior lines of chemotherapy in the advanced setting. Patients were treated with ENMD-2076 250 mg orally once daily with continuous dosing in 4-week cycles until disease progression or unacceptable toxicity occurred. The primary endpoint was 6-month clinical benefit rate (CBR), and secondary endpoints included progression-free survival, pharmacokinetic profile, safety, and biologic correlates in archival and fresh serial tumor biopsies in a subset of patients. RESULTS: Forty-one patients were enrolled. The 6-month CBR was 16.7% (95% CI, 6-32.8%) and included two partial responses. The 4-month CBR was 27.8% (95% CI, 14-45.2%), and the average duration of benefit was 6.5 cycles. Common adverse events included hypertension, fatigue, diarrhea, and nausea. Treatment with ENMD-2076 resulted in a decrease in cellular proliferation and microvessel density and an increase in p53 and p73 expression, consistent with preclinical observations. CONCLUSIONS: Single-agent ENMD-2076 treatment resulted in partial response or clinical benefit lasting more than 6 months in 16.7% of patients with pretreated, advanced, or metastatic TNBC. These results support the development of predictive biomarkers using archival and fresh tumor tissue, as well as consideration of mechanism-based combination strategies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01639248 . Registered on July 12, 2012.

Suboptimal Agreement Among Cytopathologists in Diagnosis of Malignancy Based on Endoscopic Ultrasound Needle Aspirates of Solid Pancreatic Lesions: A Validation Study.

BACKGROUND & AIMS: Despite the widespread use of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) to sample pancreatic lesions and the standardization of pancreaticobiliary cytopathologic nomenclature, there are few data on inter-observer agreement among cytopathologists evaluating pancreatic cytologic specimens obtained by EUS-FNA. We developed a scoring system to assess agreement among cytopathologists in overall diagnosis and quantitative and qualitative parameters, and evaluated factors associated with agreement. METHODS: We performed a prospective study to validate results from our pilot study that demonstrated moderate to substantial inter-observer agreement among cytopathologists for the final cytologic diagnosis. In the first phase, 3 cytopathologists refined criteria for assessment of quantity and quality measures. During phase 2, EUS-FNA specimens of solid pancreatic lesions from 46 patients were evaluated by 11 cytopathologists at 5 tertiary care centers using a standardized scoring tool. Individual quantitative and qualitative measures were scored and an overall cytologic diagnosis was determined. Clinical and EUS parameters were assessed as predictors of unanimous agreement. Inter-observer agreement (IOA) was calculated using multi-rater kappa (κ) statistics and a logistic regression model was created to identify factors associated with unanimous agreement. RESULTS: The IOA for final diagnoses, based on cytologic analysis, was moderate (κ = 0.56; 95% CI, 0.43-0.70). Kappa values did not increase when categories of suspicious for malignancy, malignant, and neoplasm were combined. IOA was slight to moderate for individual quantitative (κ = 0.007; 95% CI, -0.03 to -0.04) and qualitative parameters (κ = 0.5; 95% CI, 0.47-0.53). Jaundice was the only factor associated with agreement among all cytopathologists on multivariate analysis (odds ratio for unanimous agreement, 5.3; 95% CI, 1.1-26.89). CONCLUSIONS: There is a suboptimal level of agreement among cytopathologists in the diagnosis of malignancy based on analysis of EUS-FNA specimens obtained from solid pancreatic masses. Strategies are needed to refine the cytologic criteria for diagnosis of malignancy and enhance tissue acquisition techniques to improve diagnostic reproducibility among cytopathologists.

Increasing Number of Passes Beyond 4 Does Not Increase Sensitivity of Detection of Pancreatic Malignancy by Endoscopic Ultrasound-Guided Fine-Needle Aspiration.

BACKGROUND & AIMS: It is not clear exactly how many passes are required to determine whether pancreatic masses are malignant using endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). We aimed to define the per-pass diagnostic yield of EUS-FNA for establishing the malignancy of a pancreatic mass, and identify factors associated with detection of malignancies. METHODS: In a prospective study, 239 patients with solid pancreatic masses were randomly assigned to groups that underwent EUS-FNA, with the number of passes determined by an on-site cytopathology evaluation or set at 7 passes, at 3 tertiary referral centers. A final diagnosis of pancreatic malignancy was made based on findings from cytology, surgery, or a follow-up evaluation at least 1 year after EUS-FNA. The cumulative sensitivity of detection of malignancy by EUS-FNA was calculated after each pass; in the primary analysis, lesions categorized as malignant or suspicious were considered as positive findings. RESULTS: Pancreatic malignancies were found in 202 patients (84.5% of the study population). EUS-FNA detected malignancies with 96% sensitivity (95% confidence interval [CI], 92%-98%); 4 passes of EUS-FNA detected malignancies with 92% sensitivity (95% CI, 87%-95%). Tumor size greater than 2 cm was the only variable associated with positive results from cytology analysis (odds ratio, 7.8; 95% CI, 1.9-31.6). In masses larger than 2 cm, 4 passes of EUS-FNA detected malignancies with 93% sensitivity (95% CI, 89%-96%) and in masses ≤2 cm, 6 passes was associated with 82% sensitivity (95% CI, 61%-93%). Sensitivity of detection did not increase with increasing number of passes. CONCLUSIONS: In a prospective study, we found 4 passes of EUS-FNA to be sufficient to detect malignant pancreatic masses; increasing the number of passes did not increase the sensitivity of detection. Tumor size greater than 2 cm was associated with malignancy, and a greater number of passes may be required to evaluate masses 2 cm or less. ClinicalTrials.gov number, NCT01386931.

Metastatic Urothelial Carcinoma to the Uterine Cervix: A Case Report of a Rare Entity and Review of the Diagnostic Differential.

Urothelial carcinoma (UC) rarely metastasizes to the gynecologic tract, occurring in descending order of frequency, within the vagina, uterus, ovaries, and cervix. Significant morphologic overlap exists between primary gynecologic squamous lesions (both benign and malignant) and metastatic UC, thus potentially hindering a timely and accurate diagnosis. We present a case of UC metastatic to the uterine cervix in a 69-year-old female initially found to have noninvasive high-grade papillary UC of the bladder. Complaints of vaginal spotting lead to identification and biopsy of a mass in the uterine cervix. Histologic evaluation of the cervical mass showed a neoplastic proliferation of atypical epithelioid cells arranged in a papillary architecture. The differential in this case included primary uterine cervical tumors such as condyloma acuminatum, immature condyloma, verrucous carcinoma, warty/condylomatous carcinoma, and papillary squamotransitional cell carcinoma, as well as metastatic UC. A careful evaluation of histologic variances and a selective immunohistochemical panel allows differentiation of these tumors. We herein review the subtle, albeit significant, histologic and immunohistochemical differences of the aforementioned lesions.

Breast Cancers Found with Digital Breast Tomosynthesis: A Comparison of Pathology and Histologic Grade.

To compare the pathology and histologic grading of breast cancers detected with digital breast tomosynthesis to those found with conventional digital mammography. The institutional review board approved this study. A database search for all breast cancers diagnosed from June 2012 through December 2013 was performed. Imaging records for these cancers were reviewed and patients who had screening mammography with tomosynthesis as their initial examination were selected. Five dedicated breast imaging radiologists reviewed each of these screening mammograms to determine whether the cancer was visible on conventional digital mammography or whether tomosynthesis was needed to identify the cancer. A cancer was considered mammographically occult if all five radiologists agreed that the cancer could not be seen on conventional digital mammography. The size, pathology and histologic grading for all diagnosed breast cancers were then reviewed. The Mann-Whitney U and Fisher exact tests were utilized to determine any association between imaging findings and cancer size, pathologic type and histologic grade. Sixty-five cancers in 63 patients were identified. Ten of these cancers were considered occult on conventional digital mammography and detected with the addition of tomosynthesis. These mammographically occult cancers were significantly associated with Nottingham grade 1 histologic pathology (p = 0.02), were smaller (median size: 6 mm versus 10 mm, p = 0.07) and none demonstrated axillary nodal metastases. Breast cancers identified through the addition of tomosynthesis are associated with Nottingham grade 1 histologic pathology and prognostically more favorable than cancers identified with conventional digital mammography alone.

The clinical impact of immediate on-site cytopathology evaluation during endoscopic ultrasound-guided fine needle aspiration of pancreatic masses: a prospective multicenter randomized controlled trial.

OBJECTIVES: Observational data on the impact of on-site cytopathology evaluation (OCE) during endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) of pancreatic masses have reported conflicting results. We aimed to compare the diagnostic yield of malignancy and proportion of inadequate specimens between patients undergoing EUS-FNA of pancreatic masses with and without OCE. METHODS: In this multicenter randomized controlled trial, consecutive patients with solid pancreatic mass underwent randomization for EUS-FNA with or without OCE. The number of FNA passes in the OCE+ arm was dictated by the on-site cytopathologist, whereas seven passes were performed in OCE- arm. EUS-FNA protocol was standardized, and slides were reviewed by cytopathologists using standardized criteria for cytologic characteristics and diagnosis. RESULTS: A total of 241 patients (121 OCE+, 120 OCE-) were included. There was no difference between the two groups in diagnostic yield of malignancy (OCE+ 75.2% vs. OCE- 71.6%, P=0.45) and proportion of inadequate specimens (9.8 vs. 13.3%, P=0.31). Procedures in OCE+ group required fewer EUS-FNA passes (median, OCE+ 4 vs. OCE- 7, P<0.0001). There was no significant difference between the two groups with regard to overall procedure time, adverse events, number of repeat procedures, costs (based on baseline cost-minimization analysis), and accuracy (using predefined criteria for final diagnosis of malignancy). There was no difference between the two groups with respect to cytologic characteristics of cellularity, bloodiness, number of cells/slide, and contamination. CONCLUSIONS: Results of this study demonstrated no significant difference in the diagnostic yield of malignancy, proportion of inadequate specimens, and accuracy in patients with pancreatic mass undergoing EUS-FNA with or without OCE.

Thioredoxin interacting protein (TXNIP) is a novel tumor suppressor in thyroid cancer.

BACKGROUND: Thyroid cancer is the most common endocrine malignancy, and many patients with metastatic differentiated thyroid cancer (DTC), poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid cancer (ATC) fail to respond to conventional therapies, resulting in morbidity and mortality. Additional therapeutic targets and treatment options are needed for these patients. We recently reported that peroxisome proliferator-activated receptor gamma (PPARγ) is highly expressed in ATC and confers an aggressive phenotype when overexpressed in DTC cells. METHODS: Microarray analysis was used to identify downstream targets of PPARγ in ATC cells. Western blot analysis and immunohistochemistry (IHC) were used to assess thioredoxin interacting protein (TXNIP) expression in thyroid cancer cell lines and primary tumor specimens. Retroviral transduction was used to generate ATC cell lines that overexpress TXNIP, and assays that assess glucose uptake, viable cell proliferation, and invasion were used to characterize the in vitro properties of these cells. An orthotopic thyroid cancer mouse model was used to assess the effect of TXNIP overexpression in ATC cell lines in vivo. RESULTS: Using microarray analysis, we show that TXNIP is highly upregulated when PPARγ is depleted from ATC cells. Using Western blot analysis and IHC, we show that DTC and ATC cells exhibit differential TXNIP expression patterns. DTC cell lines and patient tumors have high TXNIP expression in contrast to low or absent expression in ATC cell lines and tumors. Overexpression of TXNIP decreases the growth of HTh74 cells compared to vector controls and inhibits glucose uptake in the ATC cell lines HTh74 and T238. Importantly, TXNIP overexpression in T238 cells results in attenuated tumor growth and decreased metastasis in an orthotopic thyroid cancer mouse model. CONCLUSIONS: Our findings indicate that TXNIP functions as a tumor suppressor in thyroid cells, and its downregulation is likely important in the transition from differentiated to advanced thyroid cancer. These studies underscore the potential of TXNIP as a novel therapeutic target and prognostic indicator in advanced thyroid cancer.

Induction of acute ectopic pancreatitis by endoscopic ultrasound with fine-needle aspiration.

Ectopic pancreas rarely causes symptoms or complications. We analyzed 2 atypical cases of ectopic pancreas associated with acute ectopic pancreatitis, 1 of which was induced by endoscopic ultrasound with fine-needle aspiration (EUS-FNA). The patients were seen at a tertiary medical center where they had undergone computed tomography, esophagogastroduodenoscopy, and EUS-FNA analyses. They initially received conservative medical treatment and were later treated by surgery. Both patients were diagnosed with ectopic pancreas of the stomach on the basis of computed tomography, esophagogastroduodenoscopy, or EUS-FNA. Surgical resection cured both patients and confirmed the diagnosis of ectopic pancreas. Acute ectopic pancreatitis is an unusual complication of ectopic pancreas that can be induced by EUS-FNA and diagnosed and cured with surgery.

Information transparency with immediate release: Oncology clinician and patient perceptions.

INTRODUCTION: As part of the 21st Century Cures Act (April 2021), electronic health information (EHI) must be immediately released to patients. In this study, we sought to evaluate clinician and patient perceptions regarding this immediate release. METHODS: After surveying 33 clinicians and 30 patients, semi-structured interviews were conducted with a subset of the initial sample, comprising 8 clinicians and 12 patients. Open-ended questions explored clinicians' and patients' perceptions of immediate release of EHI and how they adjusted to this change. RESULTS: Ten themes were identified: Interpreting Results, Strategies for Patient Interaction, Patient Experiences, Communication Strategies, Provider Limitations, Provider Experiences, Health Information Interfaces, Barriers to Patient Understanding, Types of Results, and Changes due to Immediate Release. Interviews demonstrated differences in perceived patient distress and comprehension, emphasizing the impersonal nature of electronic release and necessity for therapeutic clinician-patient communication. CONCLUSIONS: Clinicians and patients have unique insights on the role of immediate release. Understanding these perspectives will help improve communication and develop patient-centered tools (glossaries, summary pages, additional resources) to aid patient understanding of complex medical information.

Metaplastic mammary carcinoma with discrepant hormone receptor results by IHC and RT-PCR.

This is a young premenopausal woman with a T1cN0 metaplastic breast cancer that is ER/PR Allred score 3, but negative by mRNA. Our recommendations are: adjuvant chemotherapy with TAC x 6 or dose-dense doxorubicin and cyclophosphamide followed by paclitaxel (ddAC-T). Whole-breast radiation therapy would follow. The patient could try tamoxifen, although the likelihood of benefit is very small.

Fibronectin Contributes to a BRAF Inhibitor-driven Invasive Phenotype in Thyroid Cancer through EGR1, Which Can Be Blocked by Inhibition of ERK1/2.

Mutations in BRAF are common in advanced papillary and anaplastic thyroid cancer (PTC and ATC). However, patients with BRAF-mutant PTC currently lack therapies targeting this pathway. Despite the approved combination of BRAF and MEK1/2 inhibition for patients with BRAF-mutant ATC, these patients often progress. Thus, we screened a panel of BRAF-mutant thyroid cancer cell lines to identify new therapeutic strategies. We showed that thyroid cancer cells resistant to BRAF inhibition (BRAFi) exhibit an increase in invasion and a proinvasive secretome in response to BRAFi. Using reverse-phase protein array (RPPA), we identified a nearly 2-fold increase in expression of the extracellular matrix protein, fibronectin, in response to BRAFi treatment, and a corresponding 1.8- to 3.0-fold increase in fibronectin secretion. Accordingly, the addition of exogenous fibronectin phenocopied the BRAFi-induced increase in invasion while depletion of fibronectin in resistant cells resulted in loss of increased invasion. We further showed that BRAFi-induced invasion can be blocked by inhibition of ERK1/2. In a BRAFi-resistant patient-derived xenograft model, we found that dual inhibition of BRAF and ERK1/2 slowed tumor growth and decreased circulating fibronectin. Using RNA sequencing, we identified EGR1 as a top downregulated gene in response to combined BRAF/ERK1/2 inhibition, and we further showed that EGR1 is necessary for a BRAFi-induced increase in invasion and for induction of fibronectin in response to BRAFi. IMPLICATIONS: Together, these data show that increased invasion represents a new mechanism of resistance to BRAF inhibition in thyroid cancer that can be targeted with an ERK1/2 inhibitor.

Phase II trial of fulvestrant plus enzalutamide in ER+/HER2- advanced breast cancer.

This clinical trial combined fulvestrant with the anti-androgen enzalutamide in women with metastatic ER+/HER2- breast cancer (BC). Eligible patients were women with ECOG 0-2, ER+/HER2- measurable or evaluable metastatic BC. Prior fulvestrant was allowed. Fulvestrant was administered at 500 mg IM on days 1, 15, 29, and every 4 weeks thereafter. Enzalutamide was given at 160 mg po daily. Fresh tumor biopsies were required at study entry and after 4 weeks of treatment. The primary efficacy endpoint of the trial was the clinical benefit rate at 24 weeks (CBR24). The median age was 61 years (46-87); PS 1 (0-1); median of 4 prior non-hormonal and 3 prior hormonal therapies for metastatic disease. Twelve had prior fulvestrant, and 91% had visceral disease. CBR24 was 25% (7/28 evaluable). Median progression-free survival (PFS) was 8 weeks (95% CI: 2-52). Adverse events were as expected for hormonal therapy. Significant (p < 0.1) univariate relationships existed between PFS and ER%, AR%, and PIK3CA and/or PTEN mutations. Baseline levels of phospho-proteins in the mTOR pathway were more highly expressed in biopsies of patients with shorter PFS. Fulvestrant plus enzalutamide had manageable side effects. The primary endpoint of CBR24 was 25% in heavily pretreated metastatic ER+/HER2- BC. Short PFS was associated with activation of the mTOR pathway, and PIK3CA and/or PTEN mutations were associated with an increased hazard of progression. Thus, a combination of fulvestrant or other SERD plus AKT/PI3K/mTOR inhibitor with or without AR inhibition warrants investigation in second-line endocrine therapy of metastatic ER+ BC.

Mutual exclusivity of ESR1 and TP53 mutations in endocrine resistant metastatic breast cancer.

Both TP53 and ESR1 mutations occur frequently in estrogen receptor positive (ER+) metastatic breast cancers (MBC) and their distinct roles in breast cancer tumorigenesis and progression are well appreciated. Recent clinical studies discovered mutual exclusivity between TP53 and ESR1 mutations in metastatic breast cancers; however, mechanisms underlying this intriguing clinical observation remain largely understudied and unknown. Here, we explored the interplay between TP53 and ESR1 mutations using publicly available clinical and experimental data sets. We first confirmed the robust mutational exclusivity using six independent cohorts with 1,056 ER+ MBC samples and found that the exclusivity broadly applies to all ER+ breast tumors regardless of their clinical and distinct mutational features. ESR1 mutant tumors do not exhibit differential p53 pathway activity, whereas we identified attenuated ER activity and expression in TP53 mutant tumors, driven by a p53-associated E2 response gene signature. Further, 81% of these p53-associated E2 response genes are either direct targets of wild-type (WT) p53-regulated transactivation or are mutant p53-associated microRNAs, representing bimodal mechanisms of ER suppression. Lastly, we analyzed the very rare cases with co-occurrences of TP53 and ESR1 mutations and found that their simultaneous presence was also associated with reduced ER activity. In addition, tumors with dual mutations showed higher levels of total and PD-L1 positive macrophages. In summary, our study utilized multiple publicly available sources to explore the mechanism underlying the mutual exclusivity between ESR1 and TP53 mutations, providing further insights and testable hypotheses of the molecular interplay between these two pivotal genes in ER+ MBC.

Patient and clinician perceptions of the immediate release of electronic health information.

OBJECTIVES: The 21st Century Cures Act requires that institutions release all electronic health information (EHI) to patients immediately. We aimed to understand patient and clinician attitudes toward the immediate release of EHI to patients. METHODS: Patients and clinicians representing distinct specialties at a single academic medical center completed a survey to assess attitudes toward the immediate release of results. Differences between patient and clinician responses were compared using chi-square and student's t-test for categorical and continuous variables, respectively. A two-sided significance level of 0.05 was used for all statistical tests. RESULTS: 69 clinicians and 57 patients completed the survey. Both patients (89.7%) and clinicians (80.6%) agreed or strongly agreed-here after referred to as agreed, that providing patients with access to their health information is necessary in delivering high-quality care. However, 62.7% of clinicians agreed that results released immediately would be more confusing than helpful, whereas the minority of patients agreed with this statement (15.8%) (p < 0.05). Providers were also more likely to disagree that patients are comfortable independently interpreting blood work results (p < 0.05), radiology results (p < 0.05) and pathology reports (p < 0.05). With regard to timing, the majority of patients (75.1%) felt their provider should contact them within 24 h of the release of an abnormal result, whereas only 9.0% of clinicians agreed with this timeframe (p < 0.05). DISCUSSIONS: Patients and clinicians value information transparency. However, the immediate release of results is controversial, especially among clinicians. The discrepancy between patient and clinician perceptions underlines the importance of setting expectations about the communication of results. Additionally, our results emphasize the need to implement strategies to help improve patient comprehension, decrease patient distress and improve clinician workflows.

Patient comprehension of breast pathology report terminology: The need for patient-centered resources.

BACKGROUND: As health care continues to evolve toward information transparency, an increasing number of patients have access to their medical records, including result reports that were not originally designed to be patient-facing. Previous studies have demonstrated that patients have poor understanding of medical terminology. However, patient comprehension of terminology specific to breast pathology reports has not been well studied. We assessed patient understanding of common medical terms found in breast pathology reports. METHODS: A survey was administered electronically to patients scheduled for a screening mammogram within a multisite health care system. Participants were asked to objectively define and interpret 8 medical terms common to breast biopsy pathology reports. Patient perception of the utility of various educational tools was also assessed. Demographic information including health literacy, education level, previous cancer diagnosis, and primary language was collected. RESULTS: In total, 527 patients completed the survey. Terms including "malignant" and "benign" were the most correctly defined at 80% and 73%, respectively, whereas only 1% correctly defined "high grade." Factors including race/ethnicity and education level were correlated with more correct scores. Patients preferred educational tools that were specific to their diagnosis and available at the time they were reviewing their results. CONCLUSION: Patient comprehension of common medical terminology is poor. Potential assumptions of understanding based on patient factors including education, past medical history, and occupation are misinformed. With the newly mandated immediate release of information to patients, there is a pressing need to develop and integrate educational tools to support patients through all aspects of their care.

Lenvatinib Plus Anti-PD-1 Combination Therapy for Advanced Cancers: Defining Mechanisms of Resistance in an Inducible Transgenic Model of Thyroid Cancer.

Background: Combination therapy with lenvatinib plus programmed death-1 (PD-1) immune checkpoint blockades (ICBs) is under investigation in many solid tumors, including thyroid cancer. Lenvatinib is known to reduce angiogenesis and may overturn the immunosuppressive effects of vascular endothelial growth factor in the tumor microenvironment. Previous studies investigating the effects of VEGF receptor inhibition on the immune response were performed in rapidly growing tumor models where immune equilibrium is not established before treatment. We hypothesize that physiologically relevant preclinical models are necessary to define mechanisms of resistance to immune-targeted combination therapies. Methods: We utilized the TPO-CreER/BrafV600E/wt/Trp53Δex2-10/Δex2-10 inducible transgenic model of advanced thyroid cancer to investigate lenvatinib treatment in the context of an anti-PD-1 ICB. Following tumor establishment, 3.5 months postinduction, mice were treated with high- (10 mg/kg) or low-dose (2 mg/kg) lenvatinib, anti-PD-1, or combination of lenvatinib with anti-PD-1. Tumor volume and lung metastases were assessed in each group. Immune infiltrate was characterized by flow cytometry and immunohistochemistry, and TCRß sequencing was performed to further investigate the T cell response. Results: Both low- and high-dose lenvatinib reduced tumor volume, while anti-PD-1 had no effect, alone or in combination. Although both low- and high-dose lenvatinib reduced vascular density, low-dose lenvatinib was superior in controlling tumor size. Lung metastases and survival were not improved with therapy despite the effects of lenvatinib on primary tumor size. Low-dose lenvatinib treatment led to a subtle reduction in the dominant Ly6G+CD11b+ myeloid cell population and was associated with increased CD4+ T cell infiltrate and enrichment in 4-1BB+ and granzyme B+ CD4+ T cells and FoxP3+ regulatory T cells. Polyclonal T cell expansion was evident in the majority of mice, suggesting that a tumor-specific T cell response was generated. Conclusions: The effects of lenvatinib on the immune response were most pronounced in mice treated with low-dose lenvatinib, suggesting that dose should be considered in clinical application. While the immune-modulating potential of lenvatinib is encouraging, alterations in the immune milieu and T cell activation status were insufficient to sustain durable tumor regression, even with added anti-PD-1. Additional studies are necessary to develop more effective combination approaches in low-mutation burden tumors, such as thyroid cancer.