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Background Anthracycline-based chemotherapy is associated with reduced cardiorespiratory fitness in breast cancer patients. High intensity interval training (HIIT) induces greater benefits on cardiorespiratory fitness than moderate continuous aerobic exercise in patients with heart failure. The study purpose was to determine whether a HIIT intervention is a feasible exercise strategy for breast cancer patients undergoing anthracycline-based chemotherapy. Methods Thirty women were randomized to either HIIT or non-exercise control group (CON). Participants performed a maximal cycling fitness test to measure peak power output during maximal oxygen uptake (VO 2 max). The HIIT group participated in an 8-week HIIT intervention occurring 3 times weekly. Feasibility was calculated by computing (1) the average weekly minutes of HIIT over 8 weeks and (2) the number of sessions attended and multiplied by 100 (percentage of sessions). The intervention was considered feasible if more than 50% of participants completed both an average of 70% of weekly minutes (63/90 min) and attended 70% exercise sessions (17/24 sessions). Results Participants were 46.9 ± 9.8 (mean ± SD) years old, diagnosed with clinical stage II (30%) or III (63%) breast cancer. The average weekly minutes of exercise completed was 78 ± 5.1 out of 90 min. Twelve of 15 participants met both feasibility criteria, attending 19.2 ± 2.1 out of 24 sessions (82.3%). VO 2 max was maintained (19.7 ± 8.7 to 19.4 ± 6.6 ml/kg/min) in HIIT group ( p  = 0.94) while there was a significant decrease in VO 2 max (18.7 ± 7.1 to 16.1 ± 6.0 ml/kg/min) in CON group from baseline to 8 weeks ( p  = 0.001). Conclusions HIIT is a feasible exercise intervention to maintain VO 2 max in breast cancer patients receiving anthracycline-based chemotherapy. Trial registration The protocol and informed consent were approved by the institutional IRB (HS-12-00227) and registered ( ClinicalTrials.gov NCT02454777; date of registration: May 272,015).

Purpose The purpose of this study was to determine the effects of an 8-week high-intensity interval training (HIIT) intervention on vascular endothelial function, measured as brachial artery flow-mediated dilation (baFMD), and vascular wall thickness measured by carotid intima media thickness (cIMT) in breast cancer patients undergoing anthracycline-based chemotherapy. Methods Thirty women were randomized to either HIIT or non-exercise control groups (CON). The HIIT group participated in an 8-week HIIT intervention occurring three times per week on a cycle ergometer. The CON group was offered the HIIT intervention after 8 weeks. baFMD was measured from the brachial artery diameter at baseline (D0) and 1 min after cuff deflation (D1); percent change was calculated by measuring brachial artery diameter after cuff deflation relative to the baseline [baFMD = (D1 − D0)/D0 × 100]. The cIMT was obtained from the posterior wall of common carotid artery 10 mm below the carotid bulb. Paired t test and repeated measures ANCOVA were performed to assess changes in baFMD and cIMT. Results At baseline, the HIIT ( n  = 15) and CON ( n  = 15) groups did not differ by age (46.9 ± 9.8 years), BMI (31.0 ± 7.5 kg/m 2 ), and blood pressure (123.4 ± 16.8/72.3.9 ± 5.6 mmHg). Post-exercise, baFMD significantly increased [4.3; 95% confidence interval (CI): (1.5, 7.0), p  = 0.005] in HIIT versus CON group. cIMT did not significantly change [0.003, 95% CI − 0.004, 0.009), p  = 0.40] in HIIT group, while IMT significantly increased from baseline to post-intervention (0.009, 95% CI 0.004, 0.010, p  = 0.003) in CON group. Conclusion This study may suggest that HIIT improved vascular endothelial function and maintained wall thickness in breast cancer patients undergoing anthracycline-based chemotherapy. Trial registration : ClinicalTrials.gov: NCT02454777.

Background The American Society of Breast Surgeons recommends genetic testing (GT) for all women with breast cancer (BC), but implementation and uptake of GT has not been well-described. Methods A retrospective chart review was performed for newly diagnosed BC patients or patients with a newly identified recurrence of BC seen in a multidisciplinary clinic (MDBC) who were offered genetic counseling (GC) and GT. Results The 138 women attending the MDBC had a median age of 54 years and comprised non-Hispanic whites (46%), Asians (28%), Hispanics (17%), blacks (4%), and other (5%). Of the 105 (76%) patients without prior GT, 100 (95%) accepted GC, with 93 (93%) of these 100 patients undergoing GT. The patients meeting the National Comprehensive Cancer Network (NCCN) guidelines for GT were more likely to undergo GT. Testing was performed with a 67- to 84-gene panel, together with an 8- to 9-gene STAT panel if needed. Among 120 patients with reports available, including 33 patients previously tested, 15 (12%) were positive (1 BLM , 1 BRCA1 , 3 BRCA2 , 1 BRIP1 , 1 CFTR , 1 CHEK2 , 1 MUTYH , 1 PALB2 , 1 PRSS1 , 1 RAD50 , 1 RET, and 2 TP53 ), 44 (37%) were negative, and 61 (51%) had an uncertain variant. The median time to STAT results ( n = 50) was 8 days. The STAT results were available before surgery for 47 (98%) of the 48 STAT patients undergoing surgery. Conclusions New BC patients attending the MDBC demonstrated high rates of acceptance of GC and GT. The combination of GC and GT can offer timely information critical to patient risk assessment and treatment planning.

Prolongation of the activated partial thromboplastin time (aPTT) may signify an intrinsic factor deficiency or the presence of an inhibitor of coagulation, potentially placing a patient at increased risk for bleeding. However, a contact factor (ie, factor XII, prekallikrein, and high molecular weight kininogen) deficiency, which may also cause a prolonged aPTT, is not associated with clinical bleeding. A 71-year-old female had an isolated prolonged aPTT discovered during preoperative laboratory testing. Results of the initial coagulation tests demonstrated no deficiency of factors VIII, IX, or XI and no evidence for lupus anticoagulant or antiphospholipid antibodies. However, a mixing study test was suggestive of factor deficiency. Based on these results, contact factor activity tests were performed to identify any contact factor deficiency. The patient was determined to have a prekallikrein deficiency. Rare causes of isolated prolonged aPTT include contact factor deficiencies such as prekallikrein deficiency. Identification of a contact factor deficiency is clinically useful information, as it allows for a definitive assessment of bleeding risk. This case reports a rare factor deficiency and illustrates a contemporary approach to the workup of an isolated prolonged aPTT.

Abstract Docetaxel is a taxane, which is a class of chemotherapy agent used in the treatment of multiple malignancies. It is known to have gastrointestinal side effects which can range from mild symptoms such as nausea and diarrhea to more severe complications such as neutropenic enterocolitis. In the current literature, taxanes have not been described to cause upper gastrointestinal bleeding and melena. Here, we present a case of a 54-year-old woman with breast cancer who developed dizziness, fatigue, and melena after receiving chemotherapy. Esophagogastroduodenoscopy revealed diffuse gastric erosions as well as ulceration and linear superficial lesions in the duodenum; biopsies from these sites showed taxane-induced toxicity. Her bleeding resolved with medical therapy and subsequent removal of docetaxel from her chemotherapy regimen. This case identifies upper gastrointestinal bleeding as a previously undescribed side effect of docetaxel therapy. Recent docetaxel use should be included in the differential diagnosis for upper gastrointestinal bleed, and diagnosis should lead to consideration of cessation of docetaxel or substitution with another chemotherapeutic agent.

Metastatic breast cancer (mBC) patients have a high risk of progression and face poor prognosis overall, with about one third (34%) surviving five years or more. In rare instances (2–4% of cases) patients with mBC have ERBB2 (HER2) activating mutations but are ERBB2 non-amplified. Neratinib is a potent, irreversible inhibitor that binds HER2 and inhibits downstream signaling. We used the previously validated high-definition single cell assay (HDSCA) workflow to investigate the clinical significance of the liquid biopsy in ERBB2 mutant, non-amplified, post-menopausal mBC patients starting neratinib and fulvestrant combination therapy. Characterization with a comprehensive liquid biopsy methodology (HDSCA) included genomic analysis of both the cell-free DNA (cfDNA) and single circulating tumor cells (CTCs) to monitor tumor evolution and identify potential mutational variants unique to the patient’s clinical response. A limited series of five sequentially enrolled patients presented here were from the MutHER (https://www.clinicaltrials.gov, NCT01670877) or SUMMIT (https://www.clinicaltrials.gov, NCT01953926) trials. Patients had an average of 5.4 lines of therapy before enrollment, variable hormone receptor status, and ERBB2 mutations at diagnosis and during treatment. CTC enumeration alone was not sufficient to predict clinical response. Treatment pressure was shown to lead to an observable change in CTC morphology and genomic instability (GI), suggesting these parameters may inform prognosis. Single cell copy number alteration (CNA) analysis indicated that the persistence or development of a clonal population of CTCs during treatment was associated with a worse response. Hierarchical clustering analysis of the single cells across all patients and timepoints identified distinct aberrant regions shared among patients, comprised of 26 genes that are similarly affected and may be related to drug resistance. Additionally, the genomic analysis of the cfDNA, identified new mutations in ERBB2, PIK3CA, and TP53 that arose likely due to treatment pressure in a patient with poor response, further providing insights on the dynamics of the cancer genome over the course of therapy. The data presented in this small cohort study demonstrates the feasibility of real-time molecular profiling of the cellular and acellular fractions of the liquid biopsy using the HDSCA methodology. Additional studies are necessary to determine the potential use of morphometric and genomic analysis as a prognostic tool to advance personalized oncology.

Background Precision oncology is making remarkable advancements in optimizing patient care by personalizing treatments. To date, the US Food and Drug Administration (FDA) has approved poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib (Lynparza, AstraZeneca and Merck) and talazoparib (Talzenna, Pfizer Oncology Together™) for germline or somatic BRCA1/2-mutated metastatic breast cancer (BC) patients, and PI3K inhibitor alpelisib (Piqray, Novartis) plus fulvestrant for patients with hormone receptor-positive human epidermal growth factor receptor 2-negative (HR+HER2−) PIK3CA-mutated advanced BC. In addition, the FDA approved capivasertib (Trucap, AstraZeneca) for HR+HER2− locally advanced or metastatic BC patients with one or more AKT1, PIK3CA, or PTEN alterations. Finally, the FDA recently approved elacestrant (Orserdu, Stemline Therapeutics, Inc.) for postmenopausal patients with ER+ HER2− ESR1-mutated advanced or metastatic BC with disease progression following at least one line of endocrine therapy. Methods This study presents a single institutional retrospective review of genomic reports of patients with BC. Analysis of genomic reports of 1361 BC sequencing reports was performed for 1010 patients with BC from 2013 to 2023 (23% of patients had multiple reports). Eligible patients had at least one primary or metastatic tumor. Multiple sequencing platforms were used for FFPE specimens including Tempus xT targeted next-generation sequencing (NGS), Foundation One Medicine, HopeSeq, Ashion Analytics GEM ExTra, and Exact Sciences Oncomap. Liquid biopsies were performed by Guardant, Tempus, and Foundation One Medicine. Chart reviews were performed to collect patient characteristics. BRCA1/2 -mutated, metastatic BC patients who initiated treatment with olaparib or talazoparib, and PIK3CA -mutated, HR+ metastatic BC patients who initiated treatment with alpelisib were reported. In addition, patients with ESR1 or AKT1/PIK3CA/PTEN mutations were identified. Clinical outcomes, including progression-free survival (PFS) and overall survival (OS) were analyzed for BRCA1/2 and PIK3CA -mutated patients who received PARPi or alpelisib. Survival curves were generated using the Kaplan Meier method. Results A cohort of 1010 BC patients with 1361 genomic reports was identified. A total of 935/1361 (69%) specimens were formalin-fixed paraffin-embedded (FFPE) tumor biopsies and 426/1361 (31%) were liquid biopsies. Receptor status included 65% HR+HER2−, 8% HR+HER2+, 4% HR-HER2+, and 23% TNBC. Racial and ethnic distribution of these patients included 50% non-Hispanic White, 26% Hispanic, 17% Asian, 6% African American, 1% other (Native Hawaiian or Other Pacific Islander, American Indian or Alaska Native, or unknown). Sequencing platforms included 30% Tempus xT, 31% Foundation One, 10% HopeSeq, 20% GEM ExTra, and 9% Exact Sciences. Liquid biopsies included 79% Guardant, 20% Tempus, and 1% Foundation One. Of 1010 patients, the most common mutations were TP53 (44%), PIK3CA (38%), ESR1 (14%), PTEN (12%), CCND1 (11%), FGFR1 (10%), CDH1 (10%), ERBB2 (9%), MYC (9%), FGF3 (8%), GATA3 (8%), FGF19 (8%), FGF4 (7%), ARID1A (6%), RB1 (5%), BRCA2 (5%), MAP3K1 (4%), AKT1 (4%), NF1 (4%), MLL3 (4%), ZNF703 (4%), CDKN2A (4%), BRCA1 (4%), MCL1 (3%), ATM (3%), PALB2 (1%), and CHEK2 (1%). The majority of reports with tumor mutation burden (TMB) results (97%) had low or intermediate TMB. A total of 784 actionable mutations in 1010 patients were reported, including 381/1010 (38%) PIK3CA ; 144/1010 (14%) ESR1 ; 122/1010 (12%) PTEN ; 48/1010 (5%) BRCA2 ; 36/1010 (4%) BRCA1 ; 41/1010 (4%) AKT1 ; and 12/1010 (1%) PALB2. Of the 96/1010 (10%) patients with BRCA1, BRCA2, or PALB2 mutations not including variants of uncertain significance (VUS), 33/96 (34.4%) received olaparib and 3/96 (3%) received talazoparib in the metastatic setting, and 28 were eligible for response (one had toxicity, two were lost to follow-up, and two went to hospice). Median PFS was 9.0 months and median OS was 21.8 months for patients receiving PARPi. Of the 381/1010 (38%) patients with PIK3CA mutations, 84/381 (22%) received alpelisib and 41 were eligible for response (22 had toxicity, 13 were discontinued, six were lost to follow-up, and two went to hospice). Median PFS was 7.9 months and median OS was 31.2 months for patients receiving alpelisib. A total of 544/1010 (54%) patients had AKT1, PIK3CA, or PTEN mutations which are now FDA approved for capivasertib in HR+HER2− metastatic BC patients. In addition, 144/1010 (14%) patients had ESR1 mutations which are FDA approved for elacestrant in HR+HER2− metastatic BC patients. Conclusions In this study, a total of 784 clinically actionable mutations were reported for 1010 patients with genomic sequencing. Of these, 96/1010 (10%) patients had at least one actionable mutation in homologous recombination repair genes ( BRCA1, BRCA2, PALB2 ) and 36/96 (37.5%) patients received PARP inhibitors (33 olaparib and three talazoparib). In addition, 381/1010 (38%) patients had at least one clinically actionable PIK3CA mutation, and 84/381 (22%) received alpelisib. Additionally, 544/1010 (54%) of patients had either AKT1 (41/1010), PIK3CA (381/1010), or PTEN (122/1010) alterations that were FDA approved in November 2023 for capivasertib in the treatment of HR+HER2− metastatic BC (MBC) patients. Furthermore, 144/1010 (14%) patients in this study had at least one ESR1 mutation, a clinically actionable mutation that was FDA approved in January 2023 for elacestrant in the treatment of ER+HER2− MBC patients (44% detected by liquid biopsy). Future studies are needed to determine the efficacy of elacestrant and capivasertib for patients with these mutations, and to tailor strategies for optimal patient quality of life and cancer outcome.

Abstract Background Emerging studies demonstrate that some bone-modifying agents (BMAs), such as denosumab (Dmab), can modulate immune responses by increasing tumor-infiltrating T cells and expanding the T-cell repertoire. Female patients with breast cancer in particular often receive concurrent treatment with immune checkpoint inhibitors (ICI) and BMAs. However, the clinical impact of BMAs on immune-related adverse events (irAE) and cancer outcomes in patients treated with ICI remains poorly understood. Materials and methods Female patients with breast cancer treated with pembrolizumab between 2017 and 2024 were included. Patients were categorized according to BMA received: zoledronic acid (ZA), Dmab, or none. BMA therapy was considered received within a dose interval prior to ICI (12 months for ZA; 6 months for Dmab), during ICI therapy, or within 1 month of the last ICI dose. Results In a cohort of 425 female patients with breast cancer treated with pembrolizumab, 55 (12.9%) received Dmab, 31 (7.3%) received ZA, and 339 (80.0%) received no BMA. A total of 255 (60%) patients had early-stage breast cancer, and 170 (40%) had metastatic disease. After a median follow-up of 19.4 months (95% CI, 17.5-20.8), the incidence of severe irAE was higher in patients who received Dmab vs those who received no BMA (21.8% vs 11.5%, P = .04). Patients who received Dmab had higher responses (48.0%) compared to those who received ZA (31.6%) and no BMA (35.0%), although not statistically significant (P = .3). Conclusion This is the first study to suggest an increased rate of severe irAE and potential synergistic anti-tumor effect of Dmab in combination with ICI in female patients with breast cancer.

Abstract Introduction Extended-interval (EI) dosing of pembrolizumab (400 mg IV every 6 weeks) was approved across all solid tumors based on pharmacokinetic modeling and exposure-response analyses. Although EI dosing is more convenient for patients, whether the higher dose and extended dosing interval impacts immune-related adverse events (irAE) and clinical outcomes in patients with breast cancer is unknown. Methods In this retrospective cohort study, patients with breast cancer treated with pembrolizumab between 2017 and 2024 were included. Safety (irAE) and clinical outcomes including event-free survival (EFS), progression-free survival (PFS) and overall survival (OS) were compared between patients who received only standard-interval (SI) dosing (200 mg IV every 3 weeks) pembrolizumab and those who received ≥ 1 cycle of EI dosing. Results Of the 355 patients included, 59 (17%) received ≥ 1 cycle of EI and 296 (83%) received ≥ 1 cycle of only SI. Of those who received ≥ 1 cycle of pembrolizumab EI, 27 (45.8%) started with 200 mg, 7 (11.9%) started with 400 mg, 9 (15.2%) received only 400 mg, and 16 (27.1%) switched between dosing schedules. The majority (71%) of patients had early-stage disease, and 92% had triple-negative breast cancer. In patients with early-stage disease, rates of any-grade irAE were similar (p = 0.3), while grade 3 or higher irAE was lower in EI dosing versus SI (4% vs. 20%; p = 0.01). EFS and OS were similar between the two dosing regimens (p = 0.8 and p = 0.5, respectively). In patients with metastatic disease, any-grade irAE (p = 0.5), grade 3 or higher irAE (p = 0.1), PFS (p = 0.8), and OS (p = 0.5) were similar between the dosing regimens. Conclusion In this real-world study in which patients were often switched to EI dosing after initial SI therapy, safety and efficacy of EI dosing were maintained in patients with breast cancer. As more patients are treated with EI dosing, this data provides new evidence that switching to EI dosing is safe and effective, while improving medication burden for patients.