Searching for the "Holy Grail" of breast cancer recurrence risk: a narrative review of the hunt for a better biomarker and the promise of circulating tumor DNA (ctDNA).

BACKGROUND: This paper is a narrative review of a major clinical challenge at the heart of breast cancer care: determining which patients are at risk of recurrence, which require systemic therapy, and which remain at risk in the survivorship phase of care despite initial therapy. METHODS: We review the literature on prognostic and predictive biomarkers in breast cancer with a focus on detection of minimal residual disease. RESULTS: While we have many tools to estimate and refine risk that are used to individualize local and systemic therapy, we know that we continue to over treat many patients and undertreat others. Many patients also experience what is, at least in hindsight, needless fear of recurrence. In this review, we frame this dilemma for the practicing breast oncologist and discuss the search for what we term the "holy grail" of breast cancer evaluation: the ideal biomarker of residual distant disease. We review the history of attempts to address this problem and the up-to-date science on biomarkers, circulating tumor cells and circulating tumor DNA (ctDNA). CONCLUSION: This review suggests that the emerging promise of ctDNA may help resolve a crticical dilemma at the heart of breast cancer care, and improve prognostication, treatment selection, and outcomes for patients with breast cancer.

Depression and Anxiety Among English- and Spanish-Speaking Patients With Breast Cancer Receiving Radiation Therapy.

PURPOSE: An estimated 30% and 40% of patients with breast cancer experience depression and anxiety, respectively. However, distress experienced by patients with breast cancer receiving radiation therapy may vary among patients and vary at different time points. This study sought to describe the changes in levels of depression and anxiety experienced by English- and Spanish-speaking patients throughout a course of radiation therapy for breast cancer, along with the effect of different variables to better understand potential gaps. METHODS AND MATERIALS: Eligibility criteria included English- and Spanish-speaking females, aged 18 or older, undergoing radiation therapy treatment for breast cancer at 2 institutions. Pre- and posttreatment surveys were completed before and after delivery of radiation therapy. Sociodemographic characteristics collected included race, ethnicity, marital status, education level, longest residency location, religion, housing, and food insecurity. The survey ended with the standardized PHQ-4 questionnaire to assess anxiety and depression. Results were analyzed using the analysis of covariance procedure. RESULTS: A total of 160 participants completed pre- and posttreatment surveys, with an initial response rate of 100% (169 patients), though 9 were lost to follow-up. Most of the participants were nonwhite (50%), primarily married (42.5%), and had a high school or associate's level education (46.9%). The total baseline distress mean (BDM) was 2.96 and the final distress mean was 2.78. English-speaking patients comprised 82.5% (n = 132) of the sample and had a BDM of 2.91 with an adjusted change mean decrease of 0.45. Spanish-speaking patients comprised 17.5% (n = 28) of the sample, with a baseline distress mean of 3.21 and an adjusted change mean increase of 1.03 (P = .002). Housing (P = .017) and food insecurity (P = .0002) also showed increasing distress with increased insecurity at baseline. CONCLUSIONS: Patients who speak Spanish, identify as Hispanic, or are experiencing food and housing insecurity are at an increased risk for depression and anxiety, and could benefit from more support during their course of radiation therapy to minimize distress.

Metaplastic breast cancer: A review.

Metaplastic breast cancer (MpBC) is an uncommon aggressive malignancy that is associated with a poor prognosis. Due to its rarity, the relationships between the clinical and pathological features of MpBC, treatment approach, and clinical outcomes remain underexplored. In the following review article, we synthesize the existing data on the clinical, pathological and genomic features, management, and outcomes of MpBC. We also identify potential targets for future clinical trials.

Oncologists' Perspectives on Individualizing Dose Selection for Patients With Metastatic Cancer.

PURPOSE: Treatment goals for patients with metastatic cancer include prolongation and maintenance of quality of life. Patients and oncologists have questioned the current paradigm of initial dose selection for systemic therapy; however, data on oncologists' dose selection strategies and beliefs are lacking. METHODS: We conducted an electronic international survey of medical oncologists who treat patients with breast and/or gastrointestinal cancers. Survey questions addressed experiences with, and attitudes toward, dose reduction at initiation (DRI) of a new systemic therapy for patients with metastatic cancer. RESULTS: Among 3,099 eligible oncologists, 367 responded (response rate 12%). Most (52%) reported using DRI at least 10% of the time to minimize toxicities. Gastrointestinal specialists were more likely to report DRI ≥ 10% of the time (72% v 50% of generalists and 51% of breast specialists, P < .005). Of those who dose reduced ≥ 10% of the time, 89% reported discussing potential tradeoffs between efficacy and toxicity with patients. Overall, 65% agreed it is acceptable to lower starting doses to reduce side effects even if it compromises efficacy; younger clinicians were more likely to agree (P < .005). There was strong support (89%) for future trials to determine optimal effective, rather than maximum tolerated, dose. CONCLUSION: Oncology practice varies with regard to discussion and individualized selection of starting doses in the metastatic setting. This study demonstrates a need for consideration of shared decision making regarding initial dose selection and strong support among oncologists for clinical studies to define optimal dosing and best practices for individualizing care.

Quality of life, psychological distress, and prognostic perceptions in caregivers of patients with multiple myeloma.

Although caregivers of patients with multiple myeloma (MM) play a critical role in supporting their loved ones throughout the illness course, studies examining caregiver quality of life (QOL), psychological distress, and prognostic awareness are lacking. We conducted a cross-sectional, multisite study of patients undergoing treatment with MM and their caregivers. Eligible caregivers were enrolled to 1 of 3 cohorts based on lines of therapy. Caregivers completed validated questionnaires to assess their QOL, psychological distress, and perceptions of prognosis. We enrolled 127 caregivers of patients with MM (newly diagnosed [n = 43], 2-3 lines of therapy [n = 40], and ≥4 lines of therapy [n = 44]). Caregiver QOL and psychological distress did not differ by line of therapy. The rate of clinically significant anxiety, depression, and posttraumatic stress disorder symptoms were 44.1% (56/127), 15.8% (20/127), and 24.4% (31/127), respectively. When examined in dyads, caregivers reported higher rates of clinically significant anxiety (44.4% [55/124] vs 22.5% [28/124]) compared with patients with MM. Most caregivers (84.2%, 101/120) reported that the oncologist had informed them that the patient's cancer was incurable; however, only 50.9% (58/114) and 53.6% (59/110) of caregivers acknowledged the patient's cancer was terminal and incurable, respectively. Caregivers of patients undergoing treatment for MM experience substantial psychological distress across the disease continuum, particularly anxiety. The majority of caregivers of patients with MM report that knowing the patient's prognosis is extremely important and report that the oncologist told them that the patient was incurable. Nevertheless, a significant portion of caregivers believe that the patient's MM is curable.

Pilot study to assess prolonged overnight fasting in breast cancer survivors (longfast).

PURPOSE: Retrospective analysis of nightly fasting among women with breast cancer suggests that fasting < 13 h may be associated with a higher risk of breast cancer recurrence. We sought to evaluate prolonged overnight fasting (POF), an accessible nonpharmacological intervention, in a prospective feasibility study. METHODS: We designed a single-arm, pilot study to evaluate the feasibility of fasting for 13 h overnight for 12 weeks among women with a history of early-stage breast cancer survivors. Baseline and end of study assessments included measurements of body mass index (BMI), blood biomarkers, quality of life (QOL), mood, fatigue, and physical activity. Patient-reported outcome questionnaires were also administered at 6 weeks. Feasibility was defined as ≥ 60% of participants documenting fasting for 13 h on at least 70% of nights during the study period. RESULTS: Forty women with a history of breast cancer were enrolled with a median age of 60 (range 35-76) and median time since diagnosis of 4.5 years (range 0.8-20.7). At baseline, BMI was ≥ 25 in 37.5%. Ninety-five percent of participants fasted ≥ 13 h for at least 70% of study days (95% CI 83-99%). There was a statistically significant improvement in anxiety (p = 0.0007) at 6 weeks and BMI (p = 0.0072), anxiety (p = 0.0141), depression (p = 0.0048), and fatigue (p = 0.0105) at 12 weeks. There was no significant change in overall QOL, physical activity levels, or blood biomarkers at 12 weeks. CONCLUSIONS: POF is feasible among patients with a history of breast cancer and may potentially improve BMI, mood, and fatigue without detrimental effects on overall QOL.

Quality of life, psychological distress, and prognostic perceptions in patients with multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is an incurable hematologic malignancy requiring long-term, continuous therapy. Despite its chronic and unrelenting course, studies examining quality of life (QOL), psychological distress, and perceptions of prognosis by line of therapy are lacking. METHODS: The authors conducted a cross-sectional, multisite study of patients undergoing treatment for MM (excluding maintenance) between June 2020 and January 2021. The authors conducted purposeful sampling and recruited patients to 3 cohorts based on lines of therapy: 1) newly diagnosed receiving first-line therapy; 2) 2 to 3 lines; and 3) 4 or more lines. Patients completed validated questionnaires to assess their QOL, fatigue, psychological distress, and perceptions of prognosis. RESULTS: A total of 180 patients with MM were enrolled (newly diagnosed [n = 60], 2 to 3 lines [n = 60], and ≥4 lines of therapy [n = 60]). QOL, symptom burden, and fatigue scores did not differ by lines of therapy. There were no statistically significant differences in psychological distress by line of therapy. The rates of clinically significant depression, anxiety, and post-traumatic stress disorder symptoms were 23.9% (43 of 180), 23.9% (43 of 180), and 24.4% (44 of 180), respectively. Most patients (84.7%, 149 of 176) reported that their oncologist told them their cancer was incurable, but only 30.6% (53 of 173) acknowledged that they were terminally ill, and 42.0% (73 of 174) reported that they thought their cancer was incurable. CONCLUSIONS: Patients with MM undergoing treatment experience impaired QOL and elevated psychological distress across the disease continuum, regardless of line of therapy. A substantial proportion of patients with MM have significant misperceptions about their prognosis and the curability of their illness despite reporting being informed of the prognosis by their oncologist. LAY SUMMARY: This study discusses 180 patients with MM (newly diagnosed [n = 60], 2-3 lines [n = 60], and ≥4 lines of therapy [n = 60]). Quality of life, symptom burden, and fatigue scores do not differ by lines of therapy. There are also no statistically significant differences in psychological distress by line of therapy. The rates of clinically significant depression, anxiety, and post-traumatic stress disorder symptoms are 23.9%, 23.9%, and 24.4%, respectively. Most patients (84.7%) report that their oncologist told them their cancer was incurable, but only 30.6% acknowledge that they are terminally ill, and 42.0% report that they thought their cancer was incurable.

Loss of a 7q gene, CUX1, disrupts epigenetically driven DNA repair and drives therapy-related myeloid neoplasms.

Therapy-related myeloid neoplasms (t-MNs) are high-risk late effects with poorly understood pathogenesis in cancer survivors. It has been postulated that, in some cases, hematopoietic stem and progenitor cells (HSPCs) harboring mutations are selected for by cytotoxic exposures and transform. Here, we evaluate this model in the context of deficiency of CUX1, a transcription factor encoded on chromosome 7q and deleted in half of t-MN cases. We report that CUX1 has a critical early role in the DNA repair process in HSPCs. Mechanistically, CUX1 recruits the histone methyltransferase EHMT2 to DNA breaks to promote downstream H3K9 and H3K27 methylation, phosphorylated ATM retention, subsequent γH2AX focus formation and propagation, and, ultimately, 53BP1 recruitment. Despite significant unrepaired DNA damage sustained in CUX1-deficient murine HSPCs after cytotoxic exposures, they continue to proliferate and expand, mimicking clonal hematopoiesis in patients postchemotherapy. As a consequence, preexisting CUX1 deficiency predisposes mice to highly penetrant and rapidly fatal therapy-related erythroleukemias. These findings establish the importance of epigenetic regulation of HSPC DNA repair and position CUX1 as a gatekeeper in myeloid transformation.