A real-world study of treatment sequences and second-line clinical outcomes in patients with HER2-positive metastatic breast cancer in US community practice.

PURPOSE: Standard-of-care for HER2-positive metastatic breast cancer (HER2 + mBC) patients consists of trastuzumab ± pertuzumab with chemotherapy in first-line (1L), and ado-trastuzumab emtansine (T-DM1) or the more recently approved trastuzumab deruxtecan (T-DXd) in second-line (2L). Contemporary data on treatment sequencing and real-world effectiveness is limited. This study aims to report 2L treatments and outcomes among HER2 + mBC patients in the United States (US). METHODS: HER2 + mBC patients initiating 2L treatment (index date) between January 2014 and February 2021 were identified from the Syapse Learning Health Network (LHN) database. Summary statistics for patient characteristics, treatment received, reasons for 2L discontinuation and time to 2L-clinical outcomes are reported. RESULTS: Of the 312 patients initiating 2L treatment, had a median age of 59 years (interquartile range [IQR], 50-66) at the start of 2L. The majority were white (69%) and had de novo mBC (62%). Top three 2L regimens included T-DM1 ± endocrine therapy (29%), trastuzumab/pertuzumab/taxane (10%) and T-DM1/trastuzumab (8%). Around 88% discontinued 2L and 63% received subsequent treatment. Median time-to-next-treatment was 10.6 months (95% CI, 8.8-13.3) and real-world progression-free-survival was 7.9 months (95% CI, 7.0-9.9). Among 274 patients who discontinued 2L, 47% discontinued due to progression and 17% because of intolerance/toxicity, respectively. CONCLUSION: This real-world US study showed that approximately two-thirds of 2L patients received subsequent therapy and disease progression was the most common reason for 2L discontinuation highlighting the need for timely 2L treatment with the most efficacious drug to allow patients to achieve longer treatment duration and delayed progression.

Multi-omic profiling of simultaneous ductal carcinoma in situ and invasive breast cancer.

PURPOSE: The progression of ductal carcinoma in situ (DCIS) to invasive breast carcinoma (IBC) in humans is highly variable. To better understand the relationship between them, we performed a multi-omic characterization of co-occurring DCIS and IBC lesions in a cohort of individuals. METHODS: Formalin-fixed paraffin-embedded tissue samples from 50 patients with co-occurring DCIS and IBC lesions were subjected to DNA-seq and whole transcriptome RNA-seq. Paired DCIS and IBC multi-omics profiles were then interrogated for DNA mutations, gene expression profiles and pathway analysis. RESULTS: Most small variants and copy number variations were shared between co-occurring DCIS and IBC lesions, with IBC exhibiting on average a higher degree of additional mutations. However, 36% of co-occurring lesions shared no common mutations and 49% shared no common copy number variations. The most frequent genomic variants in both DCIS and IBC were PIK3CA, TP53, KMT2C, MAP3K1, GATA3 and SF3B1, with KMT2C being more frequent in DCIS and TP53 and MAP3K1 more frequent in IBC, though the numbers are too small for definitive conclusions. The most frequent copy number variations were seen in MCL1, CKSB1 and ERBB2. ERBB2 changes were not seen in IBC unless present in the corresponding DCIS. Transcriptional profiles were highly distinct between DCIS and IBC, with DCIS exhibiting upregulation of immune-related signatures, while IBC showed significant overexpression in genes and pathways associated with cell division and proliferation. Interestingly, DCIS and IBC exhibited significant differential expression of different components of extracellular matrix (ECM) formation and regulation, with DCIS showing overexpression of ECM-membrane interaction components while IBC showed upregulation of genes associated with fibronectin and invadopodia. CONCLUSION: While most co-occurring DCIS and IBC were mutationally similar and suggestive of a common clonal progenitor, transcriptionally the lesions are highly distinct, with IBC expressing key pathways that facilitate invasion and proliferation. These results are suggestive of additional levels of regulation, epigenetic or other, that facilitate the acquisition of invasive properties during tumor evolution.

Short chain fatty acids inhibit corneal inflammatory responses to TLR ligands via the ocular G-protein coupled receptor 43.

PURPOSE: Short chain fatty acids (SCFAs) produced by gut microbiota are known to play primary roles in gut homeostasis by immunomodulation partially through G-protein coupled receptors (GPR) 43. Using mouse models of TLR ligand induced keratitis, we investigated whether SCFAs and GPR43 play any regulatory roles in the pathogenesis of inflammatory responses in the eye. METHODS: Both human and mouse eyes were labeled with a specific antibody for GPR43 and imaged by a laser scanning confocal microscope. Corneal cups from naïve C57BL/6J (B6) and GPR43 knockout (KO) mice were stimulated with TLR ligands in the presence or absence of sodium butyrate overnight and then processed for RT-PCR assay for expression of GPR43 and cytokines. Keratitis was induced by Poly I:C in wild type (WT) B6, GPR43KO and chimeric mice and the disease severity was evaluated by the corneal fluorescein staining test, and infiltrating cell staining and calculating in corneal whole mount. RESULTS: GPR43 is expressed in both human and mouse eyes and the expression is bidirectionally regulated by TLR ligands and butyrate. Butyrate significantly inhibited inflammation caused by several TLR ligands such as Poly I:C, Flagellin, and CpG-ODN (TLR-3, 5 and 9 agonists, respectively) in WT, but not GPR43KO, mice. Butyrate inhibition of TLR-induced keratitis is mediated by the GPR43 expressed in tissue but not hematopoietic, cells. CONCLUSIONS: This is the first report to demonstrate of the protective effect of SCFAs on microbial keratitis, and the dynamic expression and anti-inflammatory function of GPR43 in the eye. SCFAs can modulate inflammation and immunity in the eye through GPR43.

Neoadjuvant Trebananib plus Paclitaxel-based Chemotherapy for Stage II/III Breast Cancer in the Adaptively Randomized I-SPY2 Trial-Efficacy and Biomarker Discovery.

PURPOSE: The neutralizing peptibody trebananib prevents angiopoietin-1 and angiopoietin-2 from binding with Tie2 receptors, inhibiting angiogenesis and proliferation. Trebananib was combined with paclitaxel±trastuzumab in the I-SPY2 breast cancer trial. PATIENTS AND METHODS: I-SPY2, a phase II neoadjuvant trial, adaptively randomizes patients with high-risk, early-stage breast cancer to one of several experimental therapies or control based on receptor subtypes as defined by hormone receptor (HR) and HER2 status and MammaPrint risk (MP1, MP2). The primary endpoint is pathologic complete response (pCR). A therapy "graduates" if/when it achieves 85% Bayesian probability of success in a phase III trial within a given subtype. Patients received weekly paclitaxel (plus trastuzumab if HER2-positive) without (control) or with weekly intravenous trebananib, followed by doxorubicin/cyclophosphamide and surgery. Pathway-specific biomarkers were assessed for response prediction. RESULTS: There were 134 participants randomized to trebananib and 133 to control. Although trebananib did not graduate in any signature [phase III probabilities: Hazard ratio (HR)-negative (78%), HR-negative/HER2-positive (74%), HR-negative/HER2-negative (77%), and MP2 (79%)], it demonstrated high probability of superior pCR rates over control (92%-99%) among these subtypes. Trebananib improved 3-year event-free survival (HR 0.67), with no significant increase in adverse events. Activation levels of the Tie2 receptor and downstream signaling partners predicted trebananib response in HER2-positive disease; high expression of a CD8 T-cell gene signature predicted response in HR-negative/HER2-negative disease. CONCLUSIONS: The angiopoietin (Ang)/Tie2 axis inhibitor trebananib combined with standard neoadjuvant therapy increased estimated pCR rates across HR-negative and MP2 subtypes, with probabilities of superiority >90%. Further study of Ang/Tie2 receptor axis inhibitors in validated, biomarker-predicted sensitive subtypes is warranted.

Cobimetinib Plus Vemurafenib in Patients With Solid Tumors With BRAF Mutations: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket study evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers with genomic alterations known to be drug targets. The results in a cohort of patients with solid tumors with BRAF mutations treated with cobimetinib plus vemurafenib are reported. METHODS: Eligible patients had measurable disease (RECIST v.1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as complete response (CR) or partial response (PR) or stable disease of at least 16-weeks duration (SD16+). Low-accruing histology-specific cohorts with BRAF mutations treated with cobimetinib plus vemurafenib were collapsed into a single histology-pooled cohort for this analysis. The results were evaluated on the basis of a one-sided exact binomial test with a null DC rate of 15% versus 35% (power, .82; α, .10). The secondary end points were objective response (OR), progression-free survival, overall survival, duration of response, duration of stable disease, and safety. RESULTS: Thirty-one patients with solid tumors with BRAF mutations were enrolled. Twenty-eight patients were evaluable for efficacy. Patients had tumors with BRAF V600E (n = 26), K601E (n = 2), or other (n = 3) mutations. Two patients with CR (breast and ovarian cancers; V600E), 14 with PR (13 V600E, one N581I), and three with SD16+ (two V600E, one T599_V600insT) were observed with a DC rate of 68% (P < .0001; one-sided 90% CI, 54 to 100) and an OR rate of 57% (95% CI, 37 to 76). Nineteen patients experienced ≥one drug-related grade 3-5 adverse event or serious adverse event including one death attributed to treatment-related kidney injury. CONCLUSION: Cobimetinib plus vemurafenib showed antitumor activity in patients with advanced solid tumors with BRAF V600E mutations; additional study is warranted to confirm the antitumor activity in tumors with non-V600E BRAF mutations.

The Role of Adenosine in γδ T-Cell Regulation of Th17 Responses in Experimental Autoimmune Uveitis.

Autoimmune diseases caused by T cells can arise from either T-helper 1 (Th1) or T-helper 17 (Th17)-type pathogenic T cells. However, it is unclear whether these two T-cell subsets are influenced by distinct pathogenic factors and whether treatments that are effective for Th1 responses also work for Th17 responses. To compare these two pathogenic responses, we conducted a systematic analysis in a mouse model of experimental autoimmune uveitis (EAU) to identify the factors that promote or inhibit each response and to determine their responses to various treatments. Our study found that the two types of pathogenic responses differ significantly in their pathological progressions and susceptibility to treatments. Specifically, we observed that extracellular adenosine is a crucial pathogenic molecule involved in the pathogenicity of inflammation and T-cell reactivity and that reciprocal interaction between adenosine and gamma delta (γδ) T cells plays a significant role in amplifying Th17 responses in the development of autoimmune diseases. The potential effect of targeting adenosine or adenosine receptors is analyzed regarding whether such targeting constitutes an effective approach to modulating both γδ T-cell responses and the pathogenic Th17 responses in autoimmune diseases.

Metabolic transcriptomics dictate responses of cone photoreceptors to retinitis pigmentosa.

Most mutations in retinitis pigmentosa (RP) arise in rod photoreceptors, but cone photoreceptors, responsible for high-resolution daylight and color vision, are subsequently affected, causing the most debilitating features of the disease. We used mass spectroscopy to follow 13C metabolites delivered to the outer retina and single-cell RNA sequencing to assess photoreceptor transcriptomes. The S cone metabolic transcriptome suggests engagement of the TCA cycle and ongoing response to ROS characteristic of oxidative phosphorylation, which we link to their histone modification transcriptome. Tumor necrosis factor (TNF) and its downstream effector RIP3, which drive ROS generation via mitochondrial dysfunction, are induced and activated as S cones undergo early apoptosis in RP. The long/medium-wavelength (L/M) cone transcriptome shows enhanced glycolytic capacity, which maintains their function as RP progresses. Then, as extracellular glucose eventually diminishes, L/M cones are sustained in long-term dormancy by lactate metabolism.

Persistence of patient-detected breast cancer over time: 1990-2019.

BACKGROUND: The continued presentation of patient-detected breast cancer (BC) and associated characteristics over time is understudied. METHODS: In a large institutional cohort of first primary stage 0-IV patients with BC in 1990-2019 (n = 15,827), diagnostic method (patient-detected [PtDBC] [n = 5844]; mammography-detected [MamDBC] [nondiagnostic] [n = 9248]; and physician-detected [PhysDBC] [n = 736]) and patient and tumor characteristics including age, race, TNM stage, and hormone-receptor status were reviewed. Pearson χ2 tests for bivariate comparisons and logistic regression for patient detection-associated factors were used. RESULTS: In a cohort from 1990 to 2019, the proportion aged 50-74 years (55%-63%; p < .001) and non-White race (9%-37%; p < .001) increased over time. Percentage PtDBC decreased over time but case numbers increased (1990-1999: 44% [n = 1399]; 2010-2019: 34% [n = 2349]; p < .001). Excluding stage 0, PtDBC declined from 47% to 41% over time (p < .001). In 2010-2019, 21% of cases were stage 0, 91% of which were mammography detected (n = 1439). Seventy percent of patient-detected cases were stage II-IV (stage II, 44%; stage III, 20%; stage IV, 6%; p < .001). In adjusted logistic regression, the odds of PtDBC decreased over time (2000-2009: odds ratio [OR], .65 [95% CI, .58-.72]; 2010-2019: OR, .54 [95% CI, .49-.60]), with age <40 years OR, 15.81, and Black and non-White other at 50% increased risk. CONCLUSIONS: The relative proportion of PtDBC decreased to a constant 34%-40% of total cases after 1990-1999. PtDBC case numbers increased in subsequent years (2000-2019), and were consistently higher stage. Interval cancers, mammography-screening uptake, breast health awareness of age groups outside screening guidelines, and underserved socioeconomic groups may be related to the continued significant PtDBC incidence. PLAIN LANGUAGE SUMMARY: After decades of mammography-screening availability, symptomatic patient-detected breast cancer declined over time from 44% to a persistent rate of 34% in our institutional cohort. The persistence of patient-detected breast cancer over time presents a difficult situation for patients and care givers without clear diagnosis pathways for younger and older women outside recommended screening guidelines, who often present with higher stage and more lethal characteristics. More timely diagnosis and treatment including breast health awareness, prompt presentation of breast problems, outreach to younger age and minority groups, and provision of specialized training and care delivery for symptomatic patient-detected breast cancer are needed.

Retinal Hydration Assessment With Optical Coherence Tomography: Unraveling Its Significance in Retinal Fluid Dynamics, Macular Edema and Cell Viability.

Purpose: The purpose of this study was to quantify retinal hydration (RH) levels with optical coherence tomography (OCT) and determine the extent of cellular damage resulting from intraretinal fluid alterations. Methods: We took 6.0 mm sections of the human sensory retina that were excised from 18 fresh (<24 hours) donor eyes. They were either exposed to various osmotic stresses between 90 and 305 mOsm or dehydrated under a laminar flow hood. Change in tissue weight was used to calculate the retinal water content (RWC). Image analyses were conducted on OCT between 0 and 180 minutes to assess retinal thickness (RT) and "optically empty areas" (OEAs) representing intraretinal fluid. Correlations were sought among RWC, OEA, RWC, and RT. The effect of RH on retinal cell viability (RCV) was assessed with the Live-Dead Assay. Results: RH demonstrated a stronger correlation with the OEA than plain RT measurements (r = 0.99, P < 0.001). RH-RCV interaction fits well to a bell-shaped curve. A significant proportion of retinal cells (>80%) remained viable despite the change in RH ranging between 0.87 and 1.42 times. This "safe zone" was found to be associated with a 22% increase in OEA (r = 0.99, P < 0.01). Conclusions: OCT has been demonstrated as a valuable tool for assessing RH and can be used for intraretinal fluid content analysis. RH is a better indicator of RCV compared with RT. Computing RH may improve the determination of functional outcome of intravitreal pharmacotherapeutics used for diabetic macular edema and exudative age-related macular degeneration. Translational Relevance: We link basic research and clinical care by assessing retinal hydration's impact on retinal fluid dynamics, macular edema, and cell viability.

COVID-19 related change in breast cancer diagnosis, stage, treatment, and case volume: 2019-2021.

PURPOSE: Evaluate the COVID-19 pandemic impact on breast cancer detection method, stage and treatment before, during and after health care restrictions. METHODS: In a retrospective tertiary cancer care center cohort, first primary breast cancer (BC) patients, years 2019-2021, were reviewed (n = 1787). Chi-square statistical comparisons of detection method (patient (PtD)/mammography (MamD), Stage (0-IV) and treatment by pre-pandemic time 1: 2019 + Q1 2020; peak-pandemic time 2: Q2-Q4 2020; pandemic time 3: Q1-Q4 2021 (Q = quarter) periods and logistic regression for odds ratios were used. RESULTS: BC case volume decreased 22% in 2020 (N = 533) (p = .001). MamD declined from 64% pre-pandemic to 58% peak-pandemic, and increased to 71% in 2021 (p < .001). PtD increased from 30 to 36% peak-pandemic and declined to 25% in 2021 (p < .001). Diagnosis of Stage 0/I BC declined peak-pandemic when screening mammography was curtailed due to lock-down mandates but rebounded above pre-pandemic levels in 2021. In adjusted regression, peak-pandemic stage 0/I BC diagnosis decreased 24% (OR = 0.76, 95% CI: 0.60, 0.96, p = .021) and increased 34% in 2021 (OR = 1.34, 95% CI: 1.06, 1.70, p = .014). Peak-pandemic neoadjuvant therapy increased from 33 to 38% (p < .001), primarily for surgical delay cases. CONCLUSIONS: The COVID-19 pandemic restricted health-care access, reduced mammography screening and created surgical delays. During the peak-pandemic time, due to restricted or no access to mammography screening, we observed a decrease in stage 0/I BC by number and proportion. Continued low case numbers represent a need to re-establish screening behavior and staffing.

Hormone Receptor-Positive Breast Cancer Sensitive to Pembrolizumab: Evidence of the Pathogenicity of the MLH1 Variant 1835del3.

A woman with estrogen/progesterone receptor-positive, ERBB2-negative metastatic breast cancer developed progressive disease despite treatment with multiple hormonal and chemotherapeutic modalities. She carried a germline variant of MLH1 (1835del3), also known as c.1835_1837del and v612del, the pathogenicity of which has not been conclusively determined. MLH1 staining was not seen on immunohistochemical staining of her tumor tissue. The patient experienced a >5-year dramatic response to 4 doses of pembrolizumab. Family studies revealed multiple other relatives with the MLH1 1835del3 variant, as well as multiple relatives with colon cancer. The one relative with colon cancer who underwent genetic testing demonstrated the same variant. Laboratory studies revealed that the patient's tumor showed loss of heterozygosity (LOH) in the MLH1 region, high levels of microsatellite instability, and a high tumor mutational burden. LOH in the MLH1 region, along with the remarkable clinical response to pembrolizumab treatment and the presence of the same MLH1 variant in affected relatives, supports the hypothesis that the MLH1 1835del3 variant is pathogenic. Given the patient's family history, this likely represents an uncommon presentation of Lynch syndrome. Physicians should be alert to evaluate patients for targetable genetic variants even in unlikely clinical situations such as the one described here.

Prolonged Survival of NUT Midline Carcinoma and Current Approaches to Treatment.

NUT midline carcinoma is a rare malignancy most commonly seen in adolescents and young adults. The disease presents most often in the lung or head and neck area but can be seen occasionally elsewhere. The diagnosis can be difficult and requires a high degree of suspicion with demonstration of the classic fusion rearrangement mutation of the NUTM1 gene with one of a variety of partners by immunohistochemistry, fluorescent in situ hybridization, or genomic analysis. Survival is usually only a number of months with few long-term survivors. Here we report one of the longest-known survivors of this disease treated with surgery and radiation without additional therapy. Systemic treatment approaches including the use of chemotherapy and BET and histone deacetylase inhibitors have yielded modest results. Further studies of these, as well as p300 and CDK9 inhibitors and combinations of BET inhibitors with chemotherapy or CDK 4/6 inhibitors, are being evaluated. Recent reports suggest there may be a role for immune checkpoint inhibitors, even in the absence of high tumor mutation burden or PD-L1 positivity. RNA sequencing of this patient's tumor demonstrated overexpression of multiple potentially targetable genes. Given the altered transcription that results from the causative mutation multi-omic evaluation of these tumors may uncover druggable targets for treatment.

Role of Complement in the Onset of Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) is a progressive degenerative disease of the central retina and the leading cause of severe loss of central vision in people over age 50. Patients gradually lose central visual acuity, compromising their ability to read, write, drive, and recognize faces, all of which greatly impact daily life activities. Quality of life is significantly affected in these patients, and there are worse levels of depression as a result. AMD is a complex, multifactorial disease in which age and genetics, as well as environmental factors, all play a role in its development and progression. The mechanism by which these risk factors interact and converge towards AMD are not fully understood, and therefore, drug discovery is challenging, with no successful therapeutic attempt to prevent the development of this disease. In this review, we describe the pathophysiology of AMD and review the role of complement, which is a major risk factor in the development of AMD.

TLR ligand ligation switches adenosine receptor usage of BMDCs leading to augmented Th17 responses in experimental autoimmune uveitis.

The extracellular level of adenosine increases greatly during inflammation, which modulates immune responses. We have previously reported that adenosine enhances Th17 responses while it suppresses Th1 responses. This study examined whether response of DC to adenosine contributes to the biased effect of adenosine and determined whether adenosine and TLR ligands have counteractive or synergistic effects on DC function. Our results show that adenosine is actively involved in both in vitro and in vivo activation of pathogenic T cells by DCs; however, under adenosine effect DCs' capability of promoting Th1 versus Th17 responses are dissociated. Moreover, activation of A2ARs on DCs inhibits Th1 responses whereas activation of A2BRs on DC enhances Th17 responses. An intriguing observation was that TLR engagement switches the adenosine receptor from A2ARs to A2BRs usage of bone marrow-derived dendritic cells (BMDCs) and adenosine binding to BMDCs via A2BR converts adenosine's anti-to proinflammatory effect. The dual effects of adenosine and TLR ligand on BMDCs synergistically enhances the Th17 responses whereas the dual effect on Th1 responses is antagonistic. The results imply that Th17 responses will gain dominance when inflammatory environment accumulates both TLR ligands and adenosine and the underlying mechanisms include that TLR ligand exposure has a unique effect switching adenosine receptor usage of DCs from A2ARs to A2BRs, via which Th17 responses are promoted. Our observation should improve our understanding on the balance of Th1 and Th17 responses in the pathogenesis of autoimmune and other related diseases.

Epidemiology of interstitial lung disease in patients with metastatic breast cancer at baseline and after treatment with HER2-directed therapy: a real-world data analysis.

PURPOSE: Using real-world data, interstitial lung disease (ILD) prevalence before and after HER2-directed therapy was estimated. Potential ILD risk factors in patients receiving HER2-directed therapy for metastatic breast cancer (mBC) were evaluated. METHODS: Adults with HER2-directed therapy for mBC initiated between September 25, 1998, and February 22, 2020 were, included. ILD was defined broadly as one or more of 64 lung conditions. Patients were followed until incident ILD, death, last contact, or study end. RESULTS: In total, 533 patients were identified with median age at mBC of 57, 51% had de novo mBC, 43% were ever smokers, 30% had lung metastases, 9% had thoracic radiation, 6% had chronic obstructive pulmonary disease, and 16% had prevalent ILD. ILD cumulative incidence at one year was 9% (95% CI 6%, 12%), with a median follow-up of 23 months. Smoking (HR 2.2, 95% CI 1.1, 4.8) and Black/African-American race (HR 3.4, 95% CI 1.6, 7.5) were significantly associated with ILD; HRs for preexisting lung conditions (HR 1.8, 95% CI 0.9, 3.8) and thoracic radiation (HR 2.3, 95% CI 0.8, 7.1) were not statistically significant. Prevalent ILD was associated with 13-fold greater occurrence of incident ILD. 85% of patients with prevalent or incident ILD were symptomatic. CONCLUSIONS: This real-world population of patients with mBC had a high prevalence of ILD prior to HER2-directed therapy, reflecting the multifactorial causation of interstitial lung changes. The cumulative incidence of ILD in patients receiving HER2-directed therapy for mBC augments prior reports. Symptomatic presentation suggests an opportunity for early intervention.

Bidirectional Effect of IFN-γ on Th17 Responses in Experimental Autoimmune Uveitis.

Pro- and ant-inflammatory effects of IFN-γ have been repeatedly found in various immune responses, including cancer and autoimmune diseases. In a previous study we showed that the timing of treatment determines the effect of adenosine-based immunotherapy. In this study we examined the role of IFN-γ in pathogenic Th17 responses in experimental autoimmune uveitis (EAU). We observed that IFN-γ has a bidirectional effect on Th17 responses, when tested both in vitro and in vivo. Anti-IFN-γ antibody inhibits Th17 responses when applied in the initial phase of the immune response; however, it enhances the Th17 response if administered in a later phase of EAU. In the current study we showed that IFN-γ is an important immunomodulatory molecule in γδ T cell activation, as well as in Th17 responses. These results should advance our understanding of the regulation of Th17 responses in autoimmunity.

Trastuzumab therapy duration in HER2-positive de novo metastatic breast cancer: 1999-2018.

PURPOSE: The optimal duration of first-line trastuzumab (T) treatment for de novo stage IV HER2-positive metastatic breast cancer (MBC) patients after complete response (CR) is not known. METHODS: A retrospective cohort study of de novo stage IV HER2-positive MBC patients who had trastuzumab included in their initial treatment (n = 69), 1999-2018, was conducted with follow-up for CR, progressive disease (PD), vital status, and disease-specific survival (DSS). Statistics included Kaplan-Meier plots and Cox proportional hazards models. RESULTS: Mean trastuzumab treatment time was 4.1 years (range 0.1-15). 54% of patients experienced CR at average time 9 months on treatment (n = 37). Eight CR patients discontinued T treatment after 18 months average post-CR time (range 0-86) and twenty-nine stayed on T treatment post CR [average 65 months (range 10-170)]. Average follow-up was 6 years, range 1-15 years. 5-year DSS was 92% for CR on T patients (N = 29); 88% CR off T (n = 8); 73% No CR on T (n = 14); and 29% No CR off T (n = 18) (p < 0.001). In forward Cox proportional hazards modeling, CR = yes [HzR = 0.31, (95% CI 0.14, 0.73), p = 0.007], continuous T treatment > 2 years [HzR = 0.24, (95% CI 0.10, 0.62), p = 0.003], and age < 65 [HzR = 0.29, (95% CI 0.11, 0.81), p = 0.018] were significantly associated with better DSS. CONCLUSION: Maximum trastuzumab treatment time to CR was 27 months with 2 or more years trastuzumab treatment independently associated with better survival. Survival comparisons and hazard modeling both indicate as good or better survival associated with continuous trastuzumab treatment regardless of CR status. Word count (n = 250).

Response of Leptomeningeal Metastasis of Breast Cancer With a HER2/neu Activating Variant to Tucatinib: A Case Report.

Metastatic breast cancer demonstrates HER2/neu amplification approximately 15% of the time. However, HER2 mutations, which often stimulate tumor growth, occur in only 3% to 5% of patients, and are seen more frequently in metastatic versus primary tumors. They are more frequent in lobular carcinoma, including triple-negative lobular cancer. Many of these variants are resistant to trastuzumab and lapatinib. However, neratinib can be efficacious, and recent data suggest that antibody-drug conjugates (ADCs) such as ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan may also be helpful. Laboratory and clinical data raise the possibility that simultaneous treatment with ADCs plus neratinib may be even more efficacious. Tucatinib, which has demonstrated significant activity in the central nervous system, has also been shown in vitro to be active against a number of these HER2 variants. This report describes a patient with metastatic estrogen receptor-positive, HER2-nonamplified breast cancer with an activating HER2 mutation whose tumor became resistant to neratinib as well as capecitabine, but whose subsequent leptomeningeal disease had a dramatically successful response to tucatinib plus capecitabine. As the frequency of HER2 mutations increases during the evolution of metastatic breast cancer, it is important to obtain genomic evaluation on these tumors with either repeat tissue or liquid biopsy as they progress over time.

PCM1-JAK2 Fusion Tyrosine Kinase Gene-Related Neoplasia: A Systematic Review of the Clinical Literature.

BACKGROUND: This review summarizes the case studies of PCM1-JAK2 fusion tyrosine kinase gene-related neoplasia. Recommended treatment includes JAK2 inhibitors and hematologic stem cell transplantation (HSCT), although the small number of patients has limited study of their efficacy. Herein, we present all available cases in the current searchable literature with their demographics, diagnoses, treatments, and outcomes. METHODS: PubMed, ScienceDirect, Publons, the Cochrane Library, and Google were searched with the following terms: PCM1-JAK2, ruxolitinib and myeloid/lymphoid. RESULTS: Sixty-six patients (mean age = 50, 77% male) had an initial diagnosis of myeloproliferative neoplasm (MPN) in 40, acute leukemia in 21 and T-cell cutaneous lymphoma in 5. Thirty-five patients (53%) had completed 5-year follow-up. The 5-year survival for the MPN, acute myelogenous leukemia (AML), acute lymphocytic leukemia, and lymphoma groups are 62.7, 14.9%, 40.0%, and 100%, respectively. Too few patients have been treated with ruxolitinib to draw conclusions regarding its effect on survival while the 5-year survival for MPN patients with or without HSCT was 80.2% (40.3%-94.8%) versus 51.5% (22.3%-74.6%), respectively. The T-cell cutaneous lymphoma patients have all survived at least 7 years. CONCLUSION: This rare condition may be increasingly detected with wider use of genomics. Ruxolitinib can yield hematologic and molecular remissions. However, HSCT is, at this time, the only potentially curative treatment. Useful prognostic markers are needed to determine appropriate timing for HSCT in patients with MPN. Patients presenting with acute leukemia have a poor prognosis.

Real-World Treatment Patterns and Clinical Effectiveness of Palbociclib Plus an Aromatase Inhibitor as First-Line Therapy in Advanced/Metastatic Breast Cancer: Analysis from the US Syapse Learning Health Network.

This retrospective single-arm study assessed real-world treatment patterns and clinical outcomes in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced/metastatic breast cancer (A/MBC) who received palbociclib plus an aromatase inhibitor as first-line therapy in US community health systems. Using electronic health records from the Syapse Learning Health Network, 242 patients were identified as having received first-line palbociclib plus an aromatase inhibitor between 3 February 2015, and 31 July 2019 (data cutoff 1 February 2020) resulting in a minimum potential 6-month follow-up period. In total, 56.6% of patients had de novo A/MBC at initial breast cancer diagnosis, 50.8% had bone-only disease, and 32.2% had visceral disease. Median follow-up was 22.4 months. Disease progression (26.4%) and intolerance/toxicity (14.9%) were the main reasons for treatment discontinuation. The median (95% CI) real-world progression-free survival was 31.7 (27.9-not estimable (NE)) months and 2-year estimated overall survival (OS) rate was 78.0%. In total, 25.6% of patients died; however, OS data are limited by the small population size and insufficient follow-up time. These real-world effectiveness outcomes complement findings from other real-world studies and randomized controlled trials and support palbociclib plus an aromatase inhibitor as first-line therapy for HR+/HER2- A/MBC.