Incidence and Mitigation of Corneal Pseudomicrocysts Induced by Antibody-Drug Conjugates (ADCs).

Purpose of Review: This study is to highlight the incidence of corneal pseudomicrocysts in FDA-approved antibody-drug conjugates (ADCs), and success of preventive therapies for pseudomicrocysts and related ocular surface adverse events (AEs). Recent Findings: ADCs are an emerging class of selective cancer therapies that consist of a potent cytotoxin connected to a monoclonal antibody (mAb) that targets antigens expressed on malignant cells. Currently, there are 11 FDA-approved ADCs with over 164 in clinical trials. Various AEs have been attributed to ADCs, including ocular surface AEs (keratitis/keratopathy, dry eye, conjunctivitis, blurred vision, corneal pseudomicrocysts). While the severity and prevalence of ADC-induced ocular surface AEs are well reported, the reporting of corneal pseudomicrocysts is limited, complicating the development of therapies to prevent or treat ADC-related ocular surface toxicity. Summary: Three of 11 FDA-approved ADCs have been implicated with corneal pseudomicrocysts, with incidence ranging from 41 to 100% of patients. Of the six ADCs that reported ocular surface AEs, only three had ocular substudies to investigate the benefit of preventive therapies including topical steroids, vasoconstrictors, and preservative-free lubricants. Current preventive therapies demonstrate limited efficacy at mitigating pseudomicrocysts and other ocular surface AEs.

Changes in Gender and Racial/Ethnic Diversity in US Residency Program Applications From 2018 to 2022.

Background Residency application patterns by gender and race/ethnicity offer important insights about diversity in residency recruitment. It is unknown how the COVID-19 pandemic and virtual interviewing affected these patterns. Objective We hypothesized that the introduction of virtual interviews caused an increase in applications submitted per applicant and that there may be differences by gender and race/ethnicity. Methods We extracted publicly reported Electronic Residency Application Service application data from 2018 to 2022 for 14 residency specialties with 1000 or more applicants in 2022 by self-reported gender and underrepresented in medicine (UIM) status. We compared patterns before and after virtual interviews were introduced in 2021. Results Among 401 480 residency applicants, the average number of applications submitted per applicant increased for all specialties between 2018 and 2022 across gender and race/ethnicity. Across all years, women applied to more programs than men in 5 specialties (dermatology, neurology, obstetrics/gynecology, pediatrics, and surgery), whereas men applied to more programs than women in 3 (anesthesia, family medicine, and physical medicine and rehabilitation). Across all years, non-UIM applicants applied to more programs than UIM applicants in all 14 specialties. There were no clear changes in application patterns by gender and race/ethnicity during in-person versus virtual interview years. Conclusions The average number of applications submitted per applicant increased over time across gender and race/ethnicity. In some specialties, women applied to more programs than men, and in others vice-versa, whereas non-UIM applicants applied to more programs than UIM applicants in all specialties. Virtual interviews did not change these patterns.

Characterizing attitudes related to future child-bearing in young women diagnosed with early-stage breast cancer.

PURPOSE: This study characterizes attitudes and decision-making around the desire for future children in young women newly diagnosed with early-stage breast cancer and assesses how clinical factors and perceived risk may impact these attitudes. METHODS: This is a prospective study in women < 45 years with newly diagnosed stage 1-3 breast cancer. Patients completed a REDCap survey on fertility and family-building in the setting of hypothetical risk scenarios. Patient, tumor, and treatment characteristics were collected through surveys and medical record. RESULTS: Of 140 study patients [median age = 41.4 (range 23-45)], 71 (50.7%) were interested in having children. Women interested in future childbearing were younger than those who were not interested (mean = 35.2 [SD = 5.2] vs 40.9 years [3.90], respectively, p < 0.001), and more likely to be childless (81% vs 31%, p < 0.001). 54 women (77.1% of patients interested in future children) underwent/planned to undergo oocyte/embryo cryopreservation before chemotherapy. Interest in future childbearing decreased with increasing hypothetical recurrence risk, however 17% of patients wanted to have children despite a 75-100% hypothetical recurrence risk. 24.3% of patients wanted to conceive < 2 years from diagnosis, and 35% of patients with hormone receptor positive tumors were not willing to complete 5 years of hormone therapy. CONCLUSION: Many young women diagnosed with early-stage breast cancer prioritize childbearing. Interest in having a biologic child was not associated with standard prognostic risk factors. Interest decreased with increasing hypothetical recurrence risk, though some patients remained committed to future childbearing despite near certain hypothetical risk. Individual risk assessment should be included in family-planning discussions throughout the continuum of care as it can influence decision-making.

A phase Ib/II study of eribulin in combination with cyclophosphamide in patients with advanced breast cancer.

PURPOSE: We hypothesized that eribulin combined with cyclophosphamide (EC) would be an effective combination with tolerable toxicity for the treatment of advanced breast cancer (ABC). METHODS: Patients with histologically confirmed metastatic or unresectable ABC with any number of prior lines of therapy were eligible to enroll. In the dose escalation cohort, dose level 0 was defined as eribulin 1.1 mg/m2 and cyclophosphamide 600 mg/m2, and dose level 1 was defined as eribulin 1.4 mg/m2 and cyclophosphamide 600 mg/m2. Eribulin was given on days 1 and 8 and cyclophosphamide on day 1 of a 21-day cycle. In the dose expansion cohort, enrollment was expanded at dose level 1. The primary objective was clinical benefit rate (CBR), and secondary objectives were response rate (RR), duration of response (DOR), progression-free survival (PFS), and safety. RESULTS: No dose-limiting toxicities were identified in the dose escalation cohort (n = 6). In the dose expansion cohort, an additional 38 patients were enrolled for a total of 44 patients, including 31 patients (70.4%) with hormone receptor-positive (HR +)/HER2- disease, 12 patients (27.3%) with triple-negative breast cancer (TNBC), and 1 patient (2.3%) with HR + /HER2 + disease. Patients had a median age of 56 years (range 33-82 years), 1 prior line of hormone therapy (range 0-6), and 2 prior lines of chemotherapy (range 0-7). CBR was 79.5% (35/44; 7 partial response, 28 stable disease) and the median DOR was 16.4 weeks (range 13.8-21.1 weeks). Median PFS was 16.4 weeks (95% CI: 13.8-21.1 weeks). The most common grade 3/4 adverse event was neutropenia (47.7%, n = 21). Fourteen of 26 patients (53.8%) with circulating tumor cell (CTC) data were CTC-positive ([Formula: see text] 5 CTC/7.5 mL) at baseline. Median PFS was shorter in patients who were CTC-positive vs. negative (13.1 vs 30.6 weeks, p = 0.011). CONCLUSION: In heavily pretreated patients with ABC, treatment with EC resulted in an encouraging CBR of 79.5% and PFS of 16.4 weeks, which compares favorably to single-agent eribulin. Dose reduction and delays were primarily due to neutropenia. The contribution of cyclophosphamide to eribulin remains unclear but warrants further evaluation. NCT01554371.

Can We De-escalate Therapy for HER2-Positive Metastatic Breast Cancer?

A recent phase Ib/II trial evaluated the combination of tucatinib, letrozole, and palbociclib in patients with HR+/HER2+ metastatic breast cancer, demonstrating a manageable safety profile and encouraging efficacy data. An all-oral, chemotherapy-free regimen is an appealing strategy, and could be a possible maintenance or primary therapy option in select patients. See related article by Shagisultanova et al., p. 5021.

Implantation of engineered adipocytes that outcompete tumors for resources suppresses cancer progression.

Tumors acquire an increased ability to obtain and metabolize nutrients. Here, we engineered and implanted adipocytes to outcompete tumors for nutrients and show that they can substantially reduce cancer progression. Growing cells or xenografts from several cancers (breast, colon, pancreas, prostate) alongside engineered human adipocytes or adipose organoids significantly suppresses cancer progression and reduces hypoxia and angiogenesis. Transplanting modulated adipocyte organoids in pancreatic or breast cancer mouse models nearby or distal from the tumor significantly suppresses its growth. To further showcase therapeutic potential, we demonstrate that co-culturing tumor organoids derived from human breast cancers with engineered patient-derived adipocytes significantly reduces cancer growth. Combined, our results introduce a novel cancer therapeutic approach, termed adipose modulation transplantation (AMT), that can be utilized for a broad range of cancers.

Systemic therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative early stage and metastatic breast cancer.

Hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is defined by the presence of the estrogen receptor and/or the progesterone receptor and the absence of HER2 gene amplification. HR-positive/HER2-negative breast cancer accounts for 65%-70% of all breast cancers, and incidence increases with increasing age. Treatment varies by stage, and endocrine therapy is the mainstay of treatment in both early stage and late-stage disease. Combinations with cyclin-dependent kinase 4/6 inhibitors have reduced distant recurrence in the early stage setting and improved overall survival in the metastatic setting. Chemotherapy is used based on stage and tumor biology in the early stage setting and after endocrine resistance for advanced disease. New therapies, including novel endocrine agents and antibody-drug conjugates, are now changing the treatment landscape. With the availability of new treatment options, it is important to define the optimal sequence of treatment to maximize clinical benefit while minimizing toxicity. In this review, the authors first discuss the pathologic and molecular features of HR-positive/HER2-negative breast cancer and mechanisms of endocrine resistance. Then, they discuss current and emerging therapies for both early stage and metastatic HR-positive/HER2-negative breast cancer, including treatment algorithms based on current data.

Role of Immunotherapy in Breast Cancer.

The advent of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has revolutionized the treatment of solid tumor malignancies. In breast cancer, the most robust data to date for ICI exist for triple-negative breast cancer (TNBC). Preclinical studies suggested increased antitumoral immune response in patients with TNBC undergoing ICI treatment. Early clinical trials investigated the use of ICI monotherapy in patients with metastatic TNBC with promising results, particularly in the first-line setting and for those patients whose tumors had high programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) expression. Subsequent trials evaluated the use of ICI in combination with conventional chemotherapy to enhance the host immune response. Pembrolizumab combined with chemotherapy in the KEYNOTE-355 study resulted in improved progression-free survival and overall survival benefits for patients with PD-L1 combined positive score > 10 metastatic TNBC. In early-stage disease, two phase III trials demonstrated increased rates of pathologic complete response at the time of surgery with the addition of neoadjuvant ICI to standard chemotherapy. The large KEYNOTE-522 trial showed improved event-free survival with neoadjuvant and adjuvant ICI. Several biomarkers have been identified, which may be predictive of response to ICI therapy including PD-1/PD-L1 expression, tumor mutational burden, tumor-infiltrating lymphocytes, and multigene assays capturing favorable immune cell signatures. For hormone receptor-positive and human epidermal growth factor receptor-positive breast cancer, there are ongoing studies evaluating ICI therapy in combination with chemotherapy and targeted agents. Finally, across all subtypes, several novel immunotherapeutic agents are under investigation including novel ICIs, cancer vaccines, adoptive cellular therapy, and oncolytic viruses.

Clinical characteristics and outcomes in patients with metastatic breast cancer and pseudocirrhosis: a single center retrospective cohort study.

PURPOSE: Pseudocirrhosis is a term used to describe changes in hepatic contour that mimic cirrhosis radiographically, but lack the classic pathologic features of cirrhosis. This radiographic finding is frequently found in patients with metastatic breast cancer (MBC), but the risk factors and clinical consequences are poorly understood. METHODS: In this retrospective study, we identified patients with MBC and pseudocirrhosis who were treated at a single center from 2002 to 2021. We used chart extraction and radiology review to determine demographic characteristics, treatment history, imaging features, and complications of pseudocirrhosis. RESULTS: 120 patients with MBC and pseudocirrhosis were identified with the following BC subtypes: hormone receptor (HR) positive, HER2 negative (n = 99, 82.5%), HR+/HER2+ (n = 14, 11.7%), HR- /HER2+ (n = 3, 2.5%), and triple negative (TNBC; n = 4, 3.3%). All patients had liver metastases and 82.5% (n = 99) had > 15 liver lesions. Thirty-six patients (30%) presented with de novo metastatic disease. Median time from MBC diagnosis to pseudocirrhosis was 29.2 months. 50% of patients had stable or responding disease at the time of pseudocirrhosis diagnosis. Sequelae of pseudocirrhosis included radiographic ascites (n = 97, 80.8%), gastric/esophageal varices (n = 68, 56.7%), splenomegaly (n = 26, 21.7%), GI bleeding (n = 12, 10.0%), and hepatic encephalopathy (n = 11, 9.2%). Median survival was 7.9 months after pseudocirrhosis diagnosis. Radiographic ascites was associated with shorter survival compared to no radiographic ascites (42.8 vs. 76.2 months, p = < 0.001). CONCLUSIONS: This is the largest case series of patients with MBC and pseudocirrhosis. Nearly all patients had HR+ MBC and extensive liver metastases. Survival was short after pseudocirrhosis and prognosis worse with radiographic ascites.

Intratumoral therapies and in-situ vaccination for melanoma.

Skin cancers are among the most physically accessible malignancies, so local delivery of a medication into the tumor, so-called intratumoral therapy, is an appealing route of drug administration. Intratumoral therapies have the potential to increase local drug concentration and/or attract immune cells to the local tumor microenvironment, possibly with fewer systemic side effects. A wide array of intratumoral agents have been studied to date in patients with advanced melanoma, including chemotherapeutic drugs, immune modulating agents, and cancer-directed vaccines. In this review, we will summarize the key pre-clinical and clinical data supporting the use of intratumoral therapy for advanced unresectable and metastatic melanoma. First, we will discuss the history of intratumoral immunotherapy for the treatment of melanoma and the various agents studied to date. Second, we will explore how intratumoral therapies can constitute an in situ vaccine, potentially leading to disease control both locally and systemically. Finally, we will highlight opportunities in the field and key future directions.

The role of percutaneous vertebral augmentation in patients with metastatic breast cancer: Literature review including report of two cases.

Patients with metastatic breast cancer are at high risk for developing vertebral compression fractures due to underlying bone metastases and bone density loss. Vertebral augmentation techniques including percutaneous vertebroplasty and percutaneous balloon kyphoplasty are techniques used to stabilize compression fractures and improve pain. However, rare complications from these interventions have been observed, including spinal cord compression, nerve root compression, venous cement embolism, and pulmonary cement embolism. These complications pose unique potential challenges for patients with cancer who may already have decreased lung function and potential for venous thromboembolism. In this review, we first describe the role of percutaneous vertebral augmentations in patients with metastatic cancer, with a particular focus on patients with breast cancer. Then, we describe complications of vertebral augmentation in two patients with metastatic breast cancer including long-term symptomatic and radiographic follow-up.

Emerging treatment strategies for metastatic triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancer that is often associated with an aggressive phenotype and a poor prognosis. Cytotoxic chemotherapy remains the mainstay of treatment for most patients with metastatic TNBC (mTNBC), but duration of response is often short and median overall survival is only 12-18 months. Therefore, it is critical to identify novel treatment strategies to improve outcomes for these patients. In this review article, we discuss recent advances in treatment strategies for patients with mTNBC including the use of immune checkpoint inhibitors, targeted therapies, and antibody-drug conjugates. For each topic, we summarize important preclinical and clinical data, discuss implications for clinical practice, and highlight future research directions.

Development and Evaluation of a Five-Component Toolkit for Internal Medicine Residents Applying for Subspecialty Fellowships.

Introduction: Subspecialty fellowship is a common career path for internal medicine (IM) residents, but little is published on residency program curricula for guiding residents through the process of applying to subspecialty fellowships. We describe a toolkit to guide IM residents through this process. Methods: We developed and implemented the Fellowship Application Toolkit for IM residents at the University of California, San Francisco, from 2018 to 2020. Educational strategies included live workshops, written resources, and one-to-one coaching, consisting of five components: fellowship application guidebook, Fellowship Application Information Night, alumni contact list, personal statement resources and coaches, and virtual interview workshop and mock interviews. Residents were surveyed both pre- and postintervention to evaluate these resources' use and efficacy. Results: Survey response rates were 21 of 41 (51%) in 2018, 25 of 41 (61%) in 2019, and 24 of 43 (56%) in 2020. Most respondents indicated the resources were extremely or very effective, including 30 of 36 (83%) who used the guidebook, 31 of 37 (84%) who attended the Fellowship Application Information Night, 10 of 15 (67%) who used the alumni contact list, nine of 10 (90%) who used the personal statement resources, and 12 of 14 (86%) who attended the virtual interview workshop. Respondents strongly or somewhat agreed that the overall efficacy of the residency's fellowship advising improved from pre- to postintervention (four of 17 [24%] in 2018 vs. 17 of 21 [81%] in 2020, p < .001). Discussion: Our Fellowship Application Toolkit was effective at supporting IM residents applying to fellowships.

Tissue-specific Tregs in cancer metastasis: opportunities for precision immunotherapy.

Decades of advancements in immuno-oncology have enabled the development of current immunotherapies, which provide long-term treatment responses in certain metastatic cancer patients. However, cures remain infrequent, and most patients ultimately succumb to treatment-refractory metastatic disease. Recent insights suggest that tumors at certain organ sites exhibit distinctive response patterns to immunotherapy and can even reduce antitumor immunity within anatomically distant tumors, suggesting the activation of tissue-specific immune tolerogenic mechanisms in some cases of therapy resistance. Specialized immune cells known as regulatory T cells (Tregs) are present within all tissues in the body and coordinate the suppression of excessive immune activation to curb autoimmunity and maintain immune homeostasis. Despite the high volume of research on Tregs, the findings have failed to reconcile tissue-specific Treg functions in organs, such as tolerance, tissue repair, and regeneration, with their suppression of local and systemic tumor immunity in the context of immunotherapy resistance. To improve the understanding of how the tissue-specific functions of Tregs impact cancer immunotherapy, we review the specialized role of Tregs in clinically common and challenging organ sites of cancer metastasis, highlight research that describes Treg impacts on tissue-specific and systemic immune regulation in the context of immunotherapy, and summarize ongoing work reporting clinically feasible strategies that combine the specific targeting of Tregs with systemic cancer immunotherapy. Improved knowledge of Tregs in the framework of their tissue-specific biology and clinical sites of organ metastasis will enable more precise targeting of immunotherapy and have profound implications for treating patients with metastatic cancer.

Emerging immunotherapeutic strategies for the treatment of breast cancer.

Immunotherapy has resulted in unprecedented gains in long-term outcomes for many cancer types and has revolutionized the treatment landscape of solid tumor oncology. Checkpoint inhibition in combination with chemotherapy has proven to be effective for the treatment of a subset of advanced triple-negative breast cancer in the first-line setting. This initial success is likely just the tip of the iceberg as there is much that remains unknown about how to best harness the immune system as a therapeutic strategy in all breast cancer subtypes. Therefore, numerous ongoing studies are currently underway to evaluate the safety and efficacy of immunotherapy in breast cancer. In this review, we will discuss emerging immunotherapeutic strategies for breast cancer treatment including the following: (1) Intratumoral therapies, (2) Anti-tumor vaccines, (3) B-specific T-cell engagers, and (4) Chimeric antigen receptor T-cell therapy, and (5) Emerging systemic immunotherapy strategies. For each topic, we will review the existing preclinical and clinical literature, discuss ongoing clinical trials, and highlight future directions in the field.

The Liver-Immunity Nexus and Cancer Immunotherapy.

The impact of liver metastases on immune checkpoint-inhibitor effectiveness in patients with solid-tumor malignancies has been the focus of several recent clinical and translational studies. We review the literature describing the immune functions of the liver and particularly the mechanistic observations in these studies. The initial clinical observation was that pembrolizumab appeared to be much less effective in melanoma and non-small cell lung cancer (NSCLC) patients with liver metastasis. Subsequently other clinical studies have extended and reported similar findings with programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibitors in many cancers. Two recent translational studies in animal models have dissected the mechanism of this systemic immune suppression. In both studies CD11b+ suppressive macrophages generated by liver metastasis in a two-site MC38 model appear to delete CD8+ T cells in a FasL-dependent manner. In addition, regulatory T-cell (Treg) activation was observed and contributed to the distal immunosuppression. Finally, we discuss some of the interventions reported to address liver immune suppression, such as radiation therapy, combination checkpoint blockade, and Treg depletion.