BackgroundThere are no Food and Drug Administration (FDA)-approved therapies for recurrent/metastatic thymic epithelial cancers (TECs) and current treatments with chemotherapy and immunotherapy leave considerable room for improvement. Discoidin domain receptor 1 (DDR1) is a collagen receptor expressed on tumor epithelial cells. DDR1 binding to collagen surrounding tumor cells results in highly aligned collagen fibers, and exclusion of cluster of differentiation 8 (CD8)+ T cells from the tumor (i.e., immune exclusion), precluding an effective anti-tumor response. High DDR1 expression has been observed in TECs and other epithelial tumor types. Furthermore, published data suggest that high DDR1 expression is associated with poor prognoses and lack of response to immunotherapies. The purpose of this article is to describe the results of PRTH-101 treatment in thymic cancer patients in our ongoing clinical trial.MethodsPRTH-101 is a humanized monoclonal antibody that blocks the interaction of collagen with the extracellular domain of DDR1; it is being tested in a phase 1 clinical trial (PRTH-101-0001) as a single agent (phase 1a) and in combination with pembrolizumab (phase 1b). PRTH-101 doses up to 1,600 mg have shown no dose-limiting toxicities alone or together with pembrolizumab. Clinical, pharmacokinetic, and target engagement data from 56 patients have informed a recommended phase 2 dose of 1,200 mg, which is being tested in phase 1c, with or without pembrolizumab.ResultsTo date, 16 TEC/thymoma patients have been treated with PRTH-101 at doses of 240 to 1,600 mg, 10 of whom have also received pembrolizumab; 14 had previously progressed on immunotherapy. Of seven patients in phase 1a and phase 1b who stayed on trial for more than one cycle, median progression-free survival (mPFS) is >7.7 months (2 ongoing) [>9.8 months mPFS for thymoma (1 ongoing); >6.6 months mPFS for TEC (1 ongoing)]. PFS was observed in patients receiving PRTH-101 alone or with pembrolizumab, irrespective of programmed death-ligand 1 (PD-L1) status. One previously untreated patient with metastatic TEC receiving 1,200 mg PRTH-101 with pembrolizumab, has an ongoing partial response, despite a PD-L1 combined positive score <1%. Six patients (of seven) are ongoing in phase 1c.ConclusionsDDR1 and PD-L1 expression data, combined with PFS data, suggest that PRTH-101 contributes to or is responsible for observed PFS in these patients. The data support further clinical evaluation of PRTH-101 alone and in combination with pembrolizumab for patients with recurrent/metastatic TEC.

Adding immune checkpoint inhibitors to neoadjuvant chemotherapy improves outcomes in early-stage triple-negative breast cancer (TNBC), but a fraction of patients derive benefit. Tumor-specific MHC-II (tsMHC-II) expression has been shown to be a predictive biomarker of pathological complete response (pCR) to neoadjuvant chemo-immunotherapy in early-stage TNBC. We performed biomarker analysis of the phase III NeoTRIP trial where patients were randomized to neoadjuvant carboplatin and nab-paclitaxel±atezolizumab. Imaging mass cytometry was used to assess tsMHC-II expression in tumor samples. TsMHC-II positivity was predefined as ≥5% of tumor cells expressing MHC-II, and at an 80th percentile exploratory cutoff. TsMHC-II positivity was associated with a higher pCR rate in the atezolizumab arm (OR:2.58; P = 0.016), but not in the chemotherapy-only arm (OR:1.37; P = 0.34) and these results were stronger using the exploratory cutoff. TsMHC-II expression is associated with improved response to neoadjuvant chemo-immunotherapy in early TNBC and could represent a clinically useful predictive biomarker for treatment personalization.

Chimeric antigen receptor (CAR)-T cell therapies have shown remarkable efficacies for treating otherwise intractable cancers. However, current clinically approved CAR-T therapies are limited by low antigen sensitivity, impeding their efficacy against cancers with low antigen expression. Here, to address this issue, we engineered CARs targeting CD19, CD22 and HER2 by including intrinsically disordered regions (IDRs) that promote signaling condensation. We discovered that the CAR fused with an IDR from FUS, EWS or TAF15 promoted the formation of CAR-T conjugation with cancer targets, the mechanical strength of CAR-T synapses and membrane-proximal signaling, which led to an increased release of cytotoxic factors and a higher killing activity toward low-antigen-expressing cancer cells in vitro. Moreover, the FUS IDR CAR-T induced improved antitumor effects in both blood cancer and solid tumor models. No spontaneous activation in the absence of antigen was observed. Together, our work demonstrates IDRs as a new toolset for improving CAR-T function through inducing biomolecular condensation.

This study examined the course of early alcohol abstinence symptoms across multiple clinical domains (i.e., cravings, withdrawal, mood, and cardiovascular measures) in individuals undergoing inpatient alcohol treatment and assessed whether cumulative lifetime adversity influences the severity and trajectory of these symptoms. Researchers tracked withdrawal symptoms, alcohol cravings, mood states, heart rate, and blood pressure in 34 inpatient participants at treatment admission and weekly for three to four consecutive weeks. The analysis employed two approaches: first, examining symptom presentation and progression over time in alcohol-dependent individuals using cumulative adversity as a moderating variable; second, comparing symptom patterns between alcohol-dependent participants with high versus low lifetime adversity against 38 control participants at each timepoint. Abstinence symptoms resolved by the third week of inpatient treatment across all participants. However, alcohol-dependent individuals with greater lifetime adversity exhibited significantly more severe symptom patterns compared to alcohol-dependent individuals with fewer adverse experiences. These differences persisted even when controlling for recent alcohol and tobacco use severity over the preceding 3 months. Understanding the profile and progression of early abstinence symptoms, along with stress-related moderating factors, could inform more personalized care planning. Cumulative lifetime adversity may serve as a readily measurable correlate of early abstinence severity and may be valuable for predicting alcohol treatment outcomes. Addressing the effects of cumulative lifetime adversity may serve as a target for early intervention in patients with alcohol use disorder.

Sacituzumab govitecan (SG) is a first-in-class trophoblast cell surface antigen-2-directed antibody-drug conjugate that selectively delivers a well-characterized and potent payload of SN-38 to cancer cells and the surrounding environment. In the United States, SG is indicated for unresectable, locally-advanced or metastatic triple-negative breast cancer (TNBC) and hormone receptor-positive/human epidermal growth factor receptor 2-negative (immunohistochemistry 0, 1+, or 2+/in situ hybridization-negative) breast cancer (HR+/HER2- BC). Real-world management of SG-related adverse events can vary widely from clinical studies. Therefore, it is vital to provide clinicians with first-hand experience to aid in the management and support of patients before treatment initiation. In clinical studies (IMMU-132-01, ASCENT, TROPiCS-02, and TROPHY-U-01), the pooled incidence of key adverse events was 61% for neutropenia, 64% for diarrhea, 51% for fatigue, and 45% for alopecia. Here, we discuss the incidence of neutropenia, diarrhea, fatigue, and alopecia associated with SG treatment and provide recommendations on their management based on established guidelines and personal clinical experience. We also discuss important risk factors such as UGT1A1 polymorphism and advanced age (eg, ≥65 years). From our practical experience, we present a case of a patient with TNBC experiencing neutropenia and diarrhea and another with HR+/HER2- BC experiencing diarrhea. Our review provides practicing oncologists considering SG therapy important information regarding its safe and appropriate use in real-world settings to maximize clinical benefit for patients with locally-advanced or metastatic TNBC and HR+/HER2- BC.

Mammographic surveillance is common among older women with a history of breast cancer, but little is known about imaging outcomes in this population. The goal of this study was to describe short-term outcomes after surveillance mammography among older women, including use of subsequent imaging, cancer diagnosis, and positive predictive value. This was a longitudinal cohort study using SEER-Medicare data. We followed women diagnosed with breast cancer between 2003-2007 at age 67 or older until diagnosis of a second primary breast cancer, death, or end of follow up (2019). We used claims to identify surveillance mammograms. Outcomes included subsequent imaging, second primary breast cancer diagnosis, and positive predictive value after surveillance. Outcomes were identified based on proximity to surveillance mammography. We stratified analyses by age and time since diagnosis. The cohort included 33, 607 women who received 160,637 mammograms over a median 12.1 years. Subsequent imaging was performed after 115 per 1000 mammograms (95% CI 114-117) and was similar across ages and time since diagnosis. Second primary breast cancer was diagnosed after 7.1 per 1000 mammograms (95% CI 6.7-7.5) and was similar across ages but generally higher beginning 5 years post diagnosis. Positive predictive value among women with subsequent imaging ranged from 3.7 to 9.2%. Most second primary breast cancers were either in-situ (23.3%) or stage I (57.0%). Although surveillance mammography may detect breast cancer even years after diagnosis, surveillance also leads to substantial subsequent testing. Whether continued surveillance at older ages improves health outcomes is uncertain.

The clinical and economic impact of breast cancer screening varies based on the modality, frequency, and age of the screened population. To characterize changes in use and cost of breast cancer screening for older women. Serial cross-sectional study using data from SEER-Medicare, 2009-2019. Women 67 and older enrolled in Medicare fee-for-service. Screening use and cost by age, frequency, and modality. We further categorized screening as cost-effective or cost-ineffective based on published economic analyses rather than guidelines. Cost-effective screening included biennial mammography among women < age 80, while cost-ineffective screening included annual mammography, addition of digital breast tomosynthesis (DBT), screening ultrasound, and anyscreening among women 80 and older. We estimated total annual spending on screening in Medicare fee-for-service, inflated to 2019 dollars. Our sample included a mean of 229,683 (range 222,400- 244,793) Medicare beneficiaries annually. Biennial screening was stable among women 65-79, at 11.2% (95% CI 11.0-11.4) in 2009 and 11.9% (95% CI 11.7-12.0) in 2019. Annual screening was also stable at 32.5% (95% CI 32.3-32.7) in 2009 and 30.0% (95% CI 29.8-30.2) in 2019. Among women 80 and older, screening (annual or biennial) declined from 19% (95% CI 18.8-19.3) to 12.9% (95% CI 12.7-13.2). Between 2009-2019, use of DBT rose from 0% to 70.3% of screened women. Total spending on cost-effective screening rose from $569 million per year to $735 million per year, a 29% increase. Spending on cost-ineffective screening rose from $548 million to $1.025 billion, an 87% increase. By 2019, spending on cost-ineffective screening accounted for 58% of total spending. Screening costs for older women have risen, driven by expenditures on technologies that may not be cost-effective. Reducing use of low value screening could result in savings that could be reallocated toward high value screening and follow up testing.