Blood plasma derived extracellular vesicles (BEVs): particle purification liquid chromatography (PPLC) and proteomic analysis reveals BEVs as a potential minimally invasive tool for predicting response to breast cancer treatment.

PURPOSE: Circulating blood plasma derived extracellular vesicles (BEVs) containing proteins hold promise for their use as minimally invasive biomarkers for predicting response to cancer therapy. The main goal of this study was to establish the efficiency and utility of the particle purification liquid chromatography (PPLC) BEV isolation method and evaluate the role of BEVs in predicting breast cancer (BC) patient response to neoadjuvant chemotherapy (NAC). METHODS: PPLC isolation was used to separate BEVs from non-EV contaminants and characterize BEVs from 17 BC patients scheduled to receive NAC. Using LC-MS/MS, we compared the proteome of PPLC-isolated BEVs from patients (n = 7) that achieved a pathological complete response (pCR) after NAC (responders [R]) to patients (n = 10) who did not achieve pCR (non-responders [NR]). Luminal MCF7 and basaloid MDA-MB-231 BC cells were treated with isolated BEVs and evaluated for metabolic activity by MTT assay. RESULTS: NR had elevated BEV concentrations and negative zeta potential (ζ-potential) prior to receipt of NAC. Eight proteins were enriched in BEVs of NR. GP1BA (CD42b), PECAM-1 (CD31), CAPN1, HSPB1 (HSP27), and ANXA5 were validated using western blot. MTT assay revealed BEVs from R and NR patients increased metabolic activity of MCF7 and MDA-MB-231 BC cells and the magnitude was highest in MCF7s treated with NR BEVs. CONCLUSION: PPLC-based EV isolation provides a preanalytical separation process for BEVs devoid of most contaminants. Our findings suggest that PPLC-isolated BEVs and the five associated proteins may be established as predictors of chemoresistance, and thus serve to identify NR to spare them the toxic effects of NAC.

Sulindac Improves Stiffness and Quality of Life in Women Taking Aromatase Inhibitors for Breast Cancer.

PURPOSE: To examine benefit of sulindac for relief of musculoskeletal symptoms (MSS) in patients stable on aromatase inhibitors (AIs). METHODS: Sulindac was evaluated at 150 mg twice daily for effects on MSS at 3, 6, 9, and 12 months in 50 postmenopausal women stable on AI therapy for a median of 12.5 months for hormone receptor-positive breast cancer. A separate, non-randomized group of 50 similar patients was observed for change in MSS over 12 months. MSS severity was assessed using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index and Brief Pain Inventory Short Form (BPI-SF). The Functional Assessment of Cancer Therapy-General form (FACT-G) measured quality of life (QOL). Change in MSS and QOL across time was assessed in each group using linear mixed effects models. RESULTS: Stiffness, not pain, was the main complaint at baseline. At 12 months, sulindac patients reported decreases (improvements) in mean (95% CI) Total WOMAC score [- 5.85 (- 9.73, - 1.96)] and WOMAC pain [- 5.40 (- 10.64, - 0 .18)], Stiffness [- 9.53 (- 14.98, - 4.08)] and Physical Function [- 5.61 (- 9.62, - 1.60)] subscales, but not BPI-SF worst pain. Among sulindac patients with higher baseline MSS severity, 35% experienced ≥ 50% improvement in Total WOMAC and Total FACT-G scores [6.18 (2.08, 10.27); P = 0.003]. For the observation group, MSS and QOL did not improve over 12 months, even among those with higher baseline MSS severity. CONCLUSIONS: Sulindac may relieve MSS in AI patients, especially physical function and stiffness. Randomized controlled trials should further evaluate NSAIDs on AI-MSS and AI adherence. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: NCT01761877, December, 2012.

The First Case of HER2+ Invasive Ductal Carcinoma Arising From a Breast Hamartoma and Literature Review.

Carcinomas arising from breast hamartomas are exceedingly rare. We present the first reported case of an African-American female presenting with a right breast lump and a subsequent mammogram suggestive of a hamartoma. She later underwent lumpectomy and was found to have HER2+ invasive ductal carcinoma (IDC) arising from a hamartoma. She was amenable to HER2-targeted trastuzumab, hormone therapy and adjuvant radiation but declined chemotherapy. In a review of the literature, IDC is the predominant neoplastic type found in hamartomas. The average hamartoma size at time of neoplasm diagnosis is 6.0 cm. Patients with hamartomas greater than 6.0 cm, with changes in calcification pattern; new nodules or asymmetry should be considered for additional evaluation with ultrasound, MRI and/or biopsy. HER2 status is under-reported among cases and should be evaluated in any malignancy found within hamartomas as HER-2 therapy has improved overall survival and recurrence free survival in HER2+breast cancer patients.

Practical diagnostic approaches to composite plasma cell neoplasm and low grade B-cell lymphoma/clonal infiltrates in the bone marrow.

Composite plasma cell neoplasm (PCN) and low grade B-cell lymphoma (B-NHL) in the bone marrow are uncommon and raise the differential diagnosis of B-NHL with plasmacytic differentiation and PCN with lymphoplasmacytic morphology. This can be a challenging differential diagnosis, and the distinctions are important because of differences in management. We report five cases of composite PCN with B-NHL or clonal B-cell infiltrates involving the bone marrow. By using multiple different diagnostic modalities, including immunophenotyping by flow cytometry and immunohistochemistry, cytogenetic analysis and IGH gene rearrangement studies by polymerase chain reaction, we were able to distinguish two distinct clonally unrelated neoplasms in all cases. We describe the utility and pitfalls of these different diagnostic modalities. Flow cytometric analysis with a panel of antibodies that includes CD19, CD56, CD138, CD45 and other aberrant markers commonly expressed by PCN will allow identification of clonally unrelated PCN and B-NHL in a composite neoplasm, and distinguish them from B-NHL with plasmacytic differentiation and PCN with lymphoplasmacytic morphology. Cytogenetic and molecular analyses can give false-negative or false-positive results. In summary, a multimodal approach utilizing these different tools, including clinical data, should be used to arrive at the correct diagnosis.

Utility of Stereotactic Body Radiation Therapy in Establishing Local Control for Patients With Invasive Breast Cancer Not Undergoing Definitive Surgery.

PURPOSE: Surgery is the backbone of breast cancer (BC) treatment. For patients who cannot undergo surgery, improving local control (LC) of the primary tumor is paramount. To that end, this study explored the role of stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Between 2015 and 2022, 21 nonsurgical candidates (10 metastatic, 11 stage IA-IIIC) received 23 SBRT courses to primary BC. Seven were analyzed retrospectively; 15 are currently enrolled in a prospective study. SBRT (40 Gy/5 fractions) was delivered every other day. Follow-up imaging was reviewed. Acute (≤3 months) and late toxicities were evaluated using Common Terminology Criteria for Adverse Events, version 5. LC and overall survival (OS) were estimated using Kaplan-Meier curves. RESULTS: Median age was 78.4 years (45.9-97.3). Median follow-up was 14.7 months (3.3-70.3). Median pre-SBRT index lesion size was 3.1 cm (0.5-14.5) and planning treatment volume was 32.4 cc (11.5-522.4). Initial posttreatment imaging performed at a median 4.0 months (0.6-11.9) post-SBRT demonstrated median decrease in index lesion size of 20.8% (0%-100%); SUV reduction of 65.2% (20.8%-100%). Second follow-up scans at a median 7.8 months post-SBRT showed 62% (0%-100%) and 88% (33.3%-100%) median reduction in tumor size and SUV, respectively, compared with pre-SBRT values. The estimated LC rate was 100% at 6 months and 93.3% at 12, 24, and 36 months. Local progression occurred in 1 case 9.5 months after SBRT, after an initial response. Regional progression occurred in 4 cases (17.4%) at a median 18.6 months (5.2-22.7) post-SBRT. Six patients (35.3%) developed distant progression at a median 2.7 months (0.9-16.2). The estimated OS was 85.7% at 6 months, 69.6% at 12 months, and 63.8% at 24 and 36 months. The rates of acute toxicity were G1: 47.8%, G2: 4.3%, G3: 8.7%, and G4: 0%. CONCLUSIONS: Definitive SBRT for primary BC resulted in good LC in nonsurgical patients and was well-tolerated. Considering the pattern of progression, additional approaches to improve regional/distant control should be investigated.

Biomarkers and Strain Echocardiography for the Detection of Subclinical Cardiotoxicity in Breast Cancer Patients Receiving Anthracyclines.

The optimal surveillance and management strategies for breast cancer patients receiving anthracycline therapy are limited by our incomplete understanding of the role of biomarkers heralding the onset of cardiotoxicity. The purpose of this study was to determine whether there is a temporal correlation between cardiac biomarkers and subclinical left ventricular dysfunction in breast cancer patients receiving anthracycline chemotherapy. Thirty-one females between 46 and 55 years old with breast cancer treated with anthracycline chemotherapy were prospectively enrolled. Cardiac biomarkers were correlated with echocardiography with speckle tracking at baseline, post-anthracycline therapy, and 6 months post-anthracycline chemotherapy. Subclinical cardiotoxicity was defined as ≥ 10% reduction in global longitudinal strain (GLS). There was a relative reduction in left ventricular ejection fraction (LVEF) ≥ 10% in 5/30 (17%) and 7/27 (26%) patients post-anthracycline therapy and 6 months post-anthracycline therapy, respectively. Subclinical cardiotoxicity was noted in 8/30 (27%) and 10/26 (38%) patients post-anthracycline and 6 months post-anthracycline therapy, respectively. Baseline N-terminal pro B-type natriuretic peptide (NT-proBNP) was the strongest predictor of LVEF (ρ = -0.45; p = 0.019), with post-therapy NT-proBNP values illustrating similar predictive value (ρ = -0.40; p = 0.038). Interim changes in suppression of tumorigenicity 2 (ST2) and galectin-3 correlated with a 6-month change in LVEF (ρ = -0.48; p = 0.012 and ρ = -0.45; p = 0.018, for ST2 and galectin-3, respectively). Changes in galectin-3 from baseline to mid-therapy paralleled changes in GLS. NT-proBNP, ST2, and galectin-3 correlate with reduced LVEF among breast cancer patients receiving anthracycline therapy. Additional trials focusing on a cardiac biomarker approach may provide guidance in the early diagnosis and management of anthracycline-induced cardiotoxicity.

Randomized Phase II Trial of Endocrine Therapy With or Without Ribociclib After Progression on Cyclin-Dependent Kinase 4/6 Inhibition in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: MAINTAIN Trial.

PURPOSE: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) improves progression-free survival (PFS) and overall survival (OS) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Although preclinical and clinical data demonstrate a benefit in changing ET and continuing a CDK4/6i at progression, no randomized prospective trials have evaluated this approach. METHODS: In this investigator-initiated, phase II, double-blind placebo-controlled trial in patients with HR+/HER2- MBC whose cancer progressed during ET and CDK4/6i, participants switched ET (fulvestrant or exemestane) from ET used pre-random assignment and randomly assigned 1:1 to the CDK4/6i ribociclib versus placebo. PFS was the primary end point, defined as time from random assignment to disease progression or death. Assuming a median PFS of 3.8 months with placebo, we had 80% power to detect a hazard ratio (HR) of 0.58 (corresponding to a median PFS of at least 6.5 months with ribociclib) with 120 patients randomly assigned using a one-sided log-rank test and significance level set at 2.5%. RESULTS: Of the 119 randomly assigned participants, 103 (86.5%) previously received palbociclib and 14 participants received ribociclib (11.7%). There was a statistically significant PFS improvement for patients randomly assigned to switched ET plus ribociclib (median, 5.29 months; 95% CI, 3.02 to 8.12 months) versus switched ET plus placebo (median, 2.76 months; 95% CI, 2.66 to 3.25 months) HR, 0.57 (95% CI, 0.39 to 0.85); P = .006. At 6 and 12 months, the PFS rate was 41.2% and 24.6% with ribociclib, respectively, compared with 23.9% and 7.4% with placebo. CONCLUSION: In this randomized trial, there was a significant PFS benefit for patients with HR+/HER2- MBC who switched ET and received ribociclib compared with placebo after previous CDK4/6i and different ET.

Bevacizumab increases risk for severe proteinuria in cancer patients.

Treatment with the chemotherapeutic agent bevacizumab, a humanized mAb that neutralizes vascular endothelial growth factor, can lead to proteinuria and renal damage. The risk factors and clinical outcomes of renal adverse events are not well understood. We performed a systematic review and meta-analysis of published randomized, controlled trials to assess the overall risk for severe proteinuria with bevacizumab. We analyzed data from 16 studies comprising 12,268 patients with a variety of tumors. The incidence of high-grade (grade 3 or 4) proteinuria with bevacizumab was 2.2% (95% confidence interval [CI] 1.2 to 4.3%). Compared with chemotherapy alone, bevacizumab combined with chemotherapy significantly increased the risk for high-grade proteinuria (relative risk 4.79; 95% CI 2.71 to 8.46) and nephrotic syndrome (relative risk 7.78; 95% CI 1.80 to 33.62); higher dosages of bevacizumab associated with increased risk for proteinuria. Regarding tumor type, renal cell carcinoma associated with the highest risk (cumulative incidence 10.2%). We did not detect a significant difference between platinum- and non-platinum-based concurrent chemotherapy with regard to risk for high-grade proteinuria (P = 0.39). In conclusion, the addition of bevacizumab to chemotherapy significantly increases the risk for high-grade proteinuria and nephrotic syndrome.

MRI Volume Changes of Axillary Lymph Nodes as Predictor of Pathologic Complete Responses to Neoadjuvant Chemotherapy in Breast Cancer.

INTRODUCTION: Longitudinal monitoring of breast tumor volume over the course of chemotherapy is informative of pathologic response. This study aims to determine whether axillary lymph node (aLN) volume by magnetic resonance imaging (MRI) could augment the prediction accuracy of treatment response to neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: Level-2a curated data from the I-SPY-1 TRIAL (2002-2006) were used. Patients had stage 2 or 3 breast cancer. MRI was acquired pre-, during, and post-NAC. A subset with visible aLNs on MRI was identified (N = 132). Prediction of pathologic complete response (PCR) was made using breast tumor volume changes, nodal volume changes, and combined breast tumor and nodal volume changes with sub-stratification with and without large lymph nodes (3 mL or ∼1.79 cm diameter cutoff). Receiver operating characteristic curve analysis was used to quantify prediction performance. RESULTS: The rate of change of aLN and breast tumor volume were informative of pathologic response, with prediction being most informative early in treatment (area under the curve (AUC), 0.57-0.87) compared with later in treatment (AUC, 0.50-0.75). Larger aLN volume was associated with hormone receptor negativity, with the largest nodal volume for triple negative subtypes. Sub-stratification by node size improved predictive performance, with the best predictive model for large nodes having AUC of 0.87. CONCLUSION: aLN MRI offers clinically relevant information and has the potential to predict treatment response to NAC in patients with breast cancer.

Managing dermatologic changes of targeted cancer therapy.

Failure to control these dermatologic changes can lead to lower dosages of cancer agents or an interrupted course of Tx. These steps can help you to head off trouble.

Vesical vs. extra-vesical patterns of recurrence after the treatment of urothelial upper tract tumors.

OBJECTIVE: The objective of this study was to define recurrence patterns after nephro-ureterectomy (NU) for urothelial upper tract tumor (UUTT), and to suggest guidelines for follow-up. METHODS: The effects of age, gender, UUTT grade, stage, size, location in the urinary system, and the administration of adjuvant chemotherapy on disease-free survival were assessed retrospectively. RESULTS: Fifty-three patients (mean age 62.7 years) underwent NU for UUTT and were followed with periodic cystoscopy, urinary cytology, and CT of the chest and abdomen. During a median follow-up period of 72 months, 26 patients (49%) developed tumor recurrence. Almost 95% of the recurrences occurred within the first 48 months following surgery. Two distinct patterns of recurrence were identified: vesical and extra-vesical recurrences. Vesical recurrence occurred in 19 patients (35.8%) and did not impair survival. The risk of vesical recurrence was independent of UUTT grade or stage. Patients who had Grades 1 or 2 UUTT developed only low-grade vesical recurrence, while patients with Grade 3 UUTT developed either high- or low-grade vesical recurrences. Extra-vesical recurrence occurred in 8 patients (15.1%); all had an initial Grade 3 UUTT, and were associated with short median survival. CONCLUSIONS: Patients presenting with Grades 1 or 2 UUTT are at risk of developing low-grade bladder tumors. Therefore, cystoscopic surveillance is recommended. Patients presenting with Grade 3 UUTT are at risk of developing both high- and low-grade bladder tumors as well as extra-vesical recurrence. An aggressive multimodality program including cystoscopy, urinary cytology, and CT of the chest and abdomen is advisable.

Cancer Therapy-Related Cardiac Dysfunction and Heart Failure: Part 2: Prevention, Treatment, Guidelines, and Future Directions.

Success with oncologic treatment has allowed cancer patients to experience longer cancer-free survival gains. Unfortunately, this success has been tempered by unintended and often devastating cardiac complications affecting overall patient outcomes. Cardiac toxicity, specifically the association of several cancer therapy agents with the development of left ventricular dysfunction and cardiomyopathy, is an issue of growing concern. Although the pathophysiologic mechanisms behind cardiac toxicity have been characterized, there is currently no evidence-based approach for monitoring and management of these patients. In the first of a 2-part review, we discuss the epidemiologic, pathophysiologic, risk factors, and imaging aspects of cancer therapy-related cardiac dysfunction and heart failure. In this second part, we discuss the prevention and treatment aspects in these patients and conclude with highlighting the evidence gaps and future directions for research in this area.

Cancer Therapy-Related Cardiac Dysfunction and Heart Failure: Part 1: Definitions, Pathophysiology, Risk Factors, and Imaging.

Advances in cancer therapy have resulted in significant improvement in long-term survival for many types of cancer but have also resulted in untoward side effects associated with treatment. One such complication that has become increasingly recognized is the development of cardiomyopathy and heart failure. Whether a previously healthy person from a cardiovascular perspective develops cancer therapy-related cardiac dysfunction or a high-risk cardiovascular patient requires cancer therapy, the team of oncologists and cardiologists must be better equipped with an evidence-based approach to care for these patients across the spectrum. Although the toxicities associated with various cancer therapies are well recognized, limitations to our understanding of the appropriate course of action remain. In this first of a 2-part review, we discuss the epidemiologic, pathophysiologic, risk factors, and imaging aspects of cancer therapy-related cardiac dysfunction and heart failure. In a subsequent second part, we discuss the prevention and treatment aspects, concluding with a section on evidence gap and future directions. We focus on adult patients in all stages of cancer therapy from pretreatment surveillance, to ongoing therapy, and long-term follow-up.

Concomitant angiosarcoma and lymphoproliferative disorder in solid organ transplant recipients.

An increased risk of posttransplant malignancy has been consistently reported following various solid organ transplants. The malignancies most commonly encountered are non-melanoma skin cancers, carcinomas of lung or breast and posttransplant lymphoproliferative disorders. Angiosarcoma, an uncommon vascular mesenchymal neoplasm, is rare in the posttransplant setting. This report describes two patients who developed high-grade angiosarcoma following a solid organ transplant. Notably, in both patients, the diagnosis of angiosarcoma was preceded by diagnosis of a lymphoproliferative disorder with monoclonal immunoglobulin heavy chain rearrangement.

Breast cancer clinical and translational research: analogies and implications for prostate cancer.

Breast and prostate cancer, respectively, are the most common cancers in women and in men in the United States. The management of locally advanced prostate cancer involves a multidisciplinary approach, bearing similarity to the therapeutic approach to breast cancer. Better understanding of the molecular biology of these cancers and the identification of the role played by the cancer stem cells and the tumor microenvironment may translate into better clinical decision making regarding risk classification and treatment allocation. A systematic assessment is presented of the many parallel evolutions in defining and treating high-risk breast cancer as they pertain to prostate cancer.