Faculty Bibliography

BACKGROUND:Toll-like receptor (TLR) agonists and radiation therapy hold promise for cancer immunotherapy. We conducted a phase I/II trial combining topical imiquimod (IMQ, a TLR-7 agonist) and local radiotherapy (RT) in patients with metastatic breast cancer accompanied by longitudinal transcriptional analysis of tumor biopsies. METHODS:The primary objective of the trial (NCT01421017) was to assess systemic responses by immune-related response criteria (irRC) after an 8-week cycle of topical IMQ and concurrent local RT (cohort 1). An amendment to the trial added two cohorts, both received one dose of cyclophosphamide (CTX) administered 1 week before study treatment initiation, IMQ/RT/CTX (cohort 2) and RT/CTX control (cohort 3). Cutaneous metastases were prospectively assigned to treatment with IMQ and RT (area A) or IMQ alone (area B). Secondary objectives were safety (Common Terminology Criteria for Adverse Events criteria) and local response in skin metastases. In all IMQ cohorts, tumors were biopsied before treatment and at 2 and 3 weeks. RESULTS:31 patients were enrolled (n=12, n=12, and n=7, in cohort 1, 2, and 3, respectively), with 4 out of 24 patients in the IMQ cohorts showing systemic tumor responses (two complete responses (CR) and two partial responses (PR)). No objective responses were observed in the seven patients enrolled in the control arm (RT alone). The treatment was well-tolerated, no grade 4-5 treatment-related adverse events occurred and grade 3 AEs were manageable (anemia, local pain, and local ulceration, n=1 each). Local objective responses were observed in 19/24 (9 CR and 10 PR) and 5/24 (5 PR) in areas treated with combined IMQ-RT and IMQ alone, respectively (p<0.001). All 24 patients treated with IMQ underwent serial biopsies, and 84 samples yielded sufficient material for transcriptional analyses. These revealed that the presence of a T-helper 1 functional orientation of the tumor microenvironment paralleled by the downregulation of DNA-repair genes was associated with CR after IMQ+RT, but not after IMQ alone. No post-treatment activation of immune-effector functions was observed in stable and progressing lesions. CONCLUSIONS:Our findings support the safety and clinical efficacy of combining topical IMQ with local RT for recurrent breast cancer, with evidence of local and occasional systemic antitumor activity. TRIAL REGISTRATION NUMBER/BACKGROUND:NCT01421017.

Antisemitism has been rising for decades and worsened following the events of Oct 7, 2023. Although anecdotal evidence suggests that these trends extend into the US medical community, quantitative data have been lacking. To address this gap, we quantitated publications about antisemitism, analyzed social media posts from the accounts of 220,405 healthcare professionals, and disseminated a survey to members of Jewish medical associations. Publications and social media posts about antisemitism rose > fivefold, while posts promoting antisemitic stereotypes increased 2-fourfold. Most Jewish-identifying medical students and professionals (75.4%) reported exposure to antisemitism. Together, our results suggest that antisemitism is escalating within the US healthcare community.

Throughout history, Jewish people have long been recognized for their achievements in the world of medical science. For example, prior to the Holocaust, many outstanding physicians in Germany were Jewish. However, even in the 1930s, refugee European Jewish doctors faced significant barriers when they tried to escape and practice elsewhere because of long-standing prejudices and anti-Jewish quotas in medical schools and hospitals around the world. Eventually quotas fell, and the period after World War II once again saw a tremendous growth in numbers of Jews excelling in medicine internationally. Since the Hamas attack on Israel on October 7, 2023, there has been a resurgence of antisemitism worldwide. It is especially noticeable in the world of healthcare. This article evaluates and highlights examples of antisemitism in four countries by authors from each of these jurisdictions.

PURPOSE/OBJECTIVE:Although ongoing studies are assessing the efficacy of new systemic therapies for patients with triple negative breast cancer (TNBC), the overwhelming majority have excluded patients with brain metastases (BM). Therefore, we aim to characterize systemic therapies and outcomes in a cohort of patients with TNBC and BM managed with stereotactic radiosurgery (SRS) and delineate predictors of increased survival. METHODS:We used our prospective patient registry to evaluate data from 2012 to 2023. We included patients who received SRS for TNBC-BM. A competing risk analysis was conducted to assess local and distant control. RESULTS:Forty-three patients with 262 tumors were included. The median overall survival (OS) was 16 months (95% CI 13-19 months). Predictors of increased OS after initial SRS include Breast GPA score > 1 (p < 0.001) and use of immunotherapy such as pembrolizumab (p = 0.011). The median time on immunotherapy was 8 months (IQR 4.4, 11.2). The median time to new CNS lesions after the first SRS treatment was 17 months (95% CI 12-22). The cumulative rate for development of new CNS metastases after initial SRS at 6 months, 1 year, and 2 years was 23%, 40%, and 70%, respectively. Thirty patients (70%) underwent multiple SRS treatments, with a median time of 5 months (95% CI 0.59-9.4 months) for the appearance of new CNS metastases after second SRS treatment. CONCLUSIONS:TNBC patients with BM can achieve longer survival than might have been previously anticipated with median survival now surpassing one year. The use of immunotherapy is associated with increased median OS of 23 months.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Median survival for all patients with breast cancer with brain metastases (BCBMs) has increased in the era of targeted therapy (TT) and with improved local control of intracranial tumors using stereotactic radiosurgery (SRS) and surgical resection. However, detailed characterization of the patients with long-term survival in the past 5 years remains sparse. The aim of this article is to characterize patients with BCBM who achieved long-term survival and identify factors associated with the uniquely better outcomes and to find predictors of mortality for patients with BCBM. METHODS:We reviewed 190 patients with breast cancer with 931 brain tumors receiving SRS who were followed at our institution with prospective data collection between 2012 and 2022. We analyzed clinical, molecular, and imaging data to assess relationship to outcomes and tumor control. RESULTS:The median overall survival from initial SRS and from breast cancer diagnosis was 25 months (95% CI 19-31 months) and 130 months (95% CI 100-160 months), respectively. Sixteen patients (17%) achieved long-term survival (survival ≥5 years from SRS), 9 of whom are still alive. Predictors of long-term survival included HER2+ status ( P = .041) and treatment with TT ( P = .046). A limited number of patients (11%) died of central nervous system (CNS) causes. A predictor of CNS-related death was the development of leptomeningeal disease after SRS ( P = .025), whereas predictors of non-CNS death included extracranial metastases at first SRS ( P = .017), triple-negative breast cancer ( P = .002), a Karnofsky Performance Status of <80 at first SRS ( P = .002), and active systemic disease at last follow-up ( P = .001). Only 13% of patients eventually needed whole brain radiotherapy. Among the long-term survivors, none died of CNS progression. CONCLUSION/CONCLUSIONS:Patients with BCBM can achieve long-term survival. The use of TT and HER2+ disease are associated with long-term survival. The primary cause of death was extracranial disease progression, and none of the patients living ≥5 years died of CNS-related disease.

PURPOSE/OBJECTIVE:Breast reirradiation (reRT) after breast conserving surgery (BCS) has emerged as a viable alternative to mastectomy for women presenting with recurrent or new primary breast cancer. There are limited data on safety of different fractionation regimens. This study reports safety and efficacy among women treated with repeat BCS and reRT. METHODS AND MATERIALS/METHODS:Patients who underwent repeat BCS followed by RT from 2015 to 2021 at 2 institutions were analyzed. Univariate logistic regression models were used to identify predictors of acute and late toxicities. Kaplan-Meier estimates were used to evaluate overall survival (OS), distant metastasis-free survival (DMFS) and locoregional recurrence-free survival (LR-RFS). RESULTS:Sixty-six patients were reviewed with median follow-up of 16 months (range: 3-60 months). At time of first recurrence, 41% had invasive carcinoma with a ductal carcinoma in situ (DCIS) component, 41% had invasive carcinoma alone and 18% had DCIS alone. All were clinically node negative. For the reirradiation course, 95% received partial breast irradiation (PBI) (57.5% with 1.5 Gy BID; 27% with 1.8 Gy daily; 10.5% with hypofractionation), and 5% received whole breast irradiation (1.8-2 Gy/fx), all of whom had received PBI for initial course. One patient experienced grade 3 fibrosis, and one patient experienced grade 3 telangiectasia. None had grade 4 or higher late adverse events. We found no association between the fractionation of the second course of RT or the cumulative dose (measured as EQD2) with acute or late toxicity. At 2 years, OS was 100%, DMFS was 91.6%, and LR-RFS was 100%. CONCLUSION/CONCLUSIONS:In this series of patients with recurrent or new primary breast cancer, a second breast conservation surgery followed by reirradiation was effective with no local recurrences and an acceptable toxicity profile across a range of available fractionation regimens at a median follow up of 16 months. Longer follow up is required.