Changes in vascular function and correlation with cardiotoxicity in women with newly diagnosed breast cancer undergoing HER2-directed therapy with and without anthracycline/cyclophosphamide.

Aims: The objective of this study was to assess the effect of HER2-directed therapy (HER2-Tx) on peripheral vasoreactivity and its correlation with cardiac function changes and the additive effects of anthracycline/cyclophosphamide (AC) therapy and baseline cardiovascular risk. Methods and results: Single-centre, prospective cohort study of women with newly diagnosed stage 1-3 HER2-positive breast cancer undergoing HER2-Tx +/- AC. All participants underwent baseline and 3-monthly evaluations with Endo-Peripheral Arterial Tonometry (Endo-PAT), vascular biomarkers [C-type natriuretic peptide (CNP) and neuregulin-1 beta (NRG-1ß)], and echocardiography. Cardiotoxicity was defined as a decrease in the left ventricular ejection fraction (LVEF) of >10% to a value <53%. Of the 47 patients enrolled, 20 (43%) received AC in addition to HER2-Tx. Deterioration of reactive hyperaemia index (RHI) on Endo-PAT by ≥20% was more common in patients receiving HER-Tx plus AC than HER2-Tx alone (65% vs. 22%; P = 0.003). A decrease in CNP and log NRG-1ß levels by 1 standard deviation did not differ significantly between the AC and non-AC groups (CNP: 20.0% vs. 7.4%; P = 0.20 and NRG-1ß: 15% vs. 11%; P = 0.69) nor did GLS (35% vs. 37%; P = 0.89). Patients treated with AC had a significantly lower 3D LVEF than non-AC recipients as early as 3 months after exposure (mean 59.3% (SD 3) vs. 63.8% (SD 4); P = 0.02). Reactive hyperaemia index and GLS were the only parameters correlating with LVEF change. Conclusion: Combination therapy with AC, but not HER2-Tx alone, leads to a decline in peripheral vascular and cardiac function. Larger studies will need to define more precisely the causal correlation between vascular and cardiac function changes in cancer patients.

Long-term outcomes of intraoperatively-placed applicator brachytherapy for rapid completion of breast conserving treatment: An analysis of a prospective registry data.

Background and purpose: To evaluate the long-term outcome of accelerated partial breast irradiation utilizing intraoperatively placed applicator-based brachytherapy (ABB) in early-stage breast cancer. Materials and methods: From our prospective registry, 223 patients with pTis-T2, pN0/pN1mic breast cancer were treated with ABB. The median treatment duration including surgery and ABB was 7 days. The prescribed doses were 32 Gy/8 fx BID (n = 25), 34 Gy/10 fx BID (n = 99), and 21 Gy/3 fx QD (n = 99). Endocrine therapy (ET) adherence was defined as completion of planned ET or ≥ 80% of the follow-up (FU) period. Cumulative incidence of ipsilateral breast tumor recurrence (IBTR) was estimated and influencing factors for IBTR-free survival rate (IBTRFS) were analyzed. Results: 218/223 patients had hormone receptor-positive tumors, including 38 (17.0%) with Tis and 185 (83.0%) with invasive cancer. After a median FU of 63 months, 19 (8.5%) patients had recurrence [17 (7.6%) with an IBTR]. Rates of 5-year IBTRFS and DFS were 92.2% and 91.1%, respectively. The 5-year IBTRFS rates were significantly higher for post-menopausal women (93.6% vs. 66.4%, p = 0.04), BMI < 30 kg/m2 (97.4% vs. 88.1%, p = 0.02), and ET-adherence (97.5% vs. 88.6%, p = 0.02). IBTRFS did not differ with dose regimens. Conclusions: Postmenopausal status, BMI < 30 kg/m2, and ET- adherence predicted favorable IBTRFS. Our results highlight the importance of careful patient selection for ABB and encouragement of ET compliance.

Evaluation of Germline Genetic Testing Criteria in a Hospital-Based Series of Women With Breast Cancer.

PURPOSE: To determine the sensitivity and specificity of genetic testing criteria for the detection of germline pathogenic variants in women with breast cancer. MATERIALS AND METHODS: Women with breast cancer enrolled in a breast cancer registry at a tertiary cancer center between 2000 and 2016 were evaluated for germline pathogenic variants in 9 breast cancer predisposition genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53). The performance of the National Comprehensive Cancer Network (NCCN) hereditary cancer testing criteria was evaluated relative to testing of all women as recommended by the American Society of Breast Surgeons. RESULTS: Of 3,907 women, 1,872 (47.9%) meeting NCCN criteria were more likely to carry a pathogenic variant in 9 predisposition genes compared with women not meeting criteria (9.0% v 3.5%; P < .001). Of those not meeting criteria (n = 2,035), 14 (0.7%) had pathogenic variants in BRCA1 or BRCA2. The sensitivity of NCCN criteria was 70% for 9 predisposition genes and 87% for BRCA1 and BRCA2, with a specificity of 53%. Expansion of the NCCN criteria to include all women diagnosed with breast cancer at ≤ 65 years of age achieved > 90% sensitivity for the 9 predisposition genes and > 98% sensitivity for BRCA1 and BRCA2. CONCLUSION: A substantial proportion of women with breast cancer carrying germline pathogenic variants in predisposition genes do not qualify for testing by NCCN criteria. Expansion of NCCN criteria to include all women diagnosed at ≤ 65 years of age improves the sensitivity of the selection criteria without requiring testing of all women with breast cancer.

Current Management and Treatment Options for Breast Pain.

Breast pain is a commonly experienced symptom in women of all ages and can significantly impact quality of life. Fear of cancer prompts many patients to report their pain, although risk for malignancy is low in the absence of a palpable mass or other abnormal finding on breast examination. All patients with breast pain should have a thorough history and physical examination to determine if diagnostic imaging is indicated. Management of breast pain without anatomic or radiographic abnormalities depends on pain type and severity. Often, no intervention is required. However, for women with pain that adversely impacts daily living, short-term therapies may be considered. For mild to moderate pain, a trial of conservative, nonpharmacologic strategies should be tried first. For those with severe symptoms impacting quality of life, a trial of pharmacologic therapy can be considered after appropriate counseling for medication-related adverse effects. Herein, we have provided a concise summary of a generalized approach to classification, assessment, and management of breast pain.

Utilization of Cardiac Surveillance Tests in Survivors of Breast Cancer and Lymphoma After Anthracycline-Based Chemotherapy.

BACKGROUND: The National Comprehensive Cancer Network and American Society of Clinical Oncology recommend consideration of the use of echocardiography 6 to 12 months after completion of anthracycline-based chemotherapy in at-risk populations. Assessment of BNP (B-type natriuretic peptide) has also been suggested by the American College of Cardiology/American Heart Association/Heart Failure Society of America for the identification of Stage A (at risk) heart failure patients. The real-world frequency of the use of these tests in patients after receipt of anthracycline therapy, however, has not been studied previously. METHODS AND RESULTS: In this retrospective study, using administrative claims data from the OptumLabs Data Warehouse, we identified 31 447 breast cancer and lymphoma patients (age ≥18 years) who were treated with an anthracycline in the United States between January 1, 2008 and January 31, 2018. Continuous medical and pharmacy coverage was required for at least 6 months before the initial anthracycline dose and 12 months after the final dose. Only 36.1% of patients had any type of cardiac surveillance (echocardiography, BNP, or cardiac imaging) in the year following completion of anthracycline therapy (29.7% echocardiography). Surveillance rate increased from 37.5% in 2008 to 42.7% in 2018 (25.6% in 2008 to 40.5% echocardiography in 2018). Lymphoma patients had a lower likelihood of any surveillance compared with patients with breast cancer (odds ratio, 0.79 [95% CI, 0.74-0.85]; P<0.001). Patients with preexisting diagnoses of coronary artery disease and arrhythmia had the highest likelihood of cardiac surveillance (odds ratio, 1.54 [95% CI, 1.39-1.69] and odds ratio, 1.42 [95% CI, 1.3-1.53]; P<0.001 for both), although no single comorbidity was associated with a >50% rate of surveillance. CONCLUSIONS: The majority of survivors of breast cancer and lymphoma who have received anthracycline-based chemotherapy do not undergo cardiac surveillance after treatment, including those with a history of cardiovascular comorbidities, such as heart failure.

Attenuated peripheral endothelial function among women treated with aromatase inhibitors for breast cancer.

PURPOSE: Data on long-term cardiovascular effects of aromatase inhibitors (AIs) are limited and conflicting. We sought to evaluate the effect of AIs on peripheral endothelial function in patients with breast cancer. PATIENTS AND METHODS: This is an observational, prospective study of postmenopausal women with breast cancer who were enrolled at the initiation of cancer treatment. All participants underwent baseline and 6-12 months of follow-up, with peripheral endothelial function testing to measure reactive hyperemia index (RHI). The primary aim was to assess endothelial function deterioration between baseline and follow-up. The secondary aim was to assess the correlation of cardiovascular risk factors with RHI change in women treated with versus without AIs. RESULTS: Among 97 patients, mean (SD) age was 66 (7) years; 59 (61%) women had AI treatment, and 38 women did not (control group). There were no significant differences in baseline characteristics between the groups. Mean (SD) RHI at baseline in the treatment group did not differ significantly from that in the control group [2.2 (0.6) vs. 2.1 (0.5); P=0.15]. The mean (SD) time between baseline and follow-up studies was 262 (60) days. RHI deterioration, evaluated as a dichotomous variable with a 20% cutoff, was significantly more common in the AI group [17 (29%) vs. 4 (11%); P=0.04]. After adjusting for age, treatment with AIs was significantly associated with an RHI deterioration of at least 20% from baseline (odds ratio: 3.6; 95% confidence interval: 1.10-12.07; P=0.03). Further, in the intervention group, women with at least three traditional cardiovascular risk factors were more likely to have RHI deterioration compared to women with λ2 risk factors [10 (42%) vs. 7 (20%); P=0.04]. Amongst women with three or more cardiovascular risk factors, the percentage with RHI deterioration was higher in the AI group than the control group [10/24 (42%) vs. 3/22 (14%); P=0.04], whereas in women with up to two risk factors, the percentage with RHI deterioration was similar between the groups [7/35 (20%) vs. 1/16 (6%); P=0.21]. CONCLUSION: This study suggests that AIs may be associated with vascular injury. The effect is more pronounced among women with a higher baseline cardiovascular risk factor burden. These findings have potentially important implications, particularly among women at high risk for cardiovascular disease who are treated with AIs for hormone receptor-positive breast cancer.

Two-dimensional speckle tracking echocardiography predicts early subclinical cardiotoxicity associated with anthracycline-trastuzumab chemotherapy in patients with breast cancer.

BACKGROUND: Combined anthracycline-trastuzumab chemotherapy has been associated with LV dysfunction. We aimed to assess early changes in left ventricular (LV) and right ventricular (RV) mechanics associated with combined anthracycline-trastuzumab treatment for breast cancer. As well as explore whether early changes in 2-dimensional (2D)-speckle tracking echocardiography (STE) could predict later chemotherapy-induced cardiotoxicity. METHODS: Sixty-six patients with breast cancer who received anthracycline-trastuzumab treatment were included (mean [±SD] age, 52 [9] years). Echocardiograms were available for analysis with 2D-STE at the following time points: pretreatment (T0), first cycle (T1), and second cycle (T2) of combined chemotherapy. All patients had a normal pretreatment LV ejection fraction (LVEF). Cardiotoxicity was defined as a decrease in LVEF of at least 10 percentage points from baseline on follow-up echocardiography. RESULTS: Cardiotoxicity developed in 13 of the 66 patients (20%). The mean (±SD) LVEF at T0 was 66% (±6); at T1 60% (±7); and at T2, 54% (±6). For the 53 patients without cardiotoxicity, the LVEF was 65% (±4%) at T0, 63% (±5%) at T1, and 62% (±4) at T2. Global longitudinal strain (GLS) at T1 was the strongest indicator of subsequent cardiotoxicity (area under the curve, 0.85; cutoff value, - 14.06; sensitivity, 91%; specificity, 83%; P = .003). Compared with baseline (T0), left ventricular longitudinal strain, LV circumferential strain, circumferential peak systolic strain rate (SR), circumferential peak early diastolic SR, right ventricular longitudinal strain, and longitudinal peak systolic SR at T1 and T2 were reduced significantly in patients with cardiotoxicity (P < .05). CONCLUSIONS: Anthracycline-trastuzumab treatment leads to early deterioration of LV GLS, circumferential strain, and systolic SR. Right ventricular GLS and SR were also affected. Early changes in GLS are good predictors of subsequent development of anthracycline-trastuzumab-induced cardiotoxicity.

Cardiovascular Risk in Breast Cancer Patients Receiving Estrogen or Progesterone Antagonists.

PURPOSE OF REVIEW: The purpose of this review is to summarize the current literature on estrogen and progesterone antagonists and their effects on the cardiovascular system. RECENT FINDINGS: Estrogen and progesterone antagonists reduce cancer-related recurrence and mortality in women with ER-positive breast cancer. Recent studies, however, suggest that women with early stage breast cancer are more likely to die of cardiovascular disease than recurrent breast cancer. Estrogen antagonists have been shown to reduce endothelial function, to increase lipid profiles and to alter body composition accelerating atherosclerotic changes. While clinical trial data demonstrates mixed results of the impact of estrogen antagonists on cardiovascular risk, there is a growing body of evidence that estrogen suppression and estrogen antagonists result in biologic effects on the endothelium, altering lipid profiles and accelerating the risk of atherosclerosis. Further longitudinal work however is needed.

Incidence, Diagnosis, and Treatment of Cardiac Toxicity from Trastuzumab in Patients with Breast Cancer.

PURPOSE OF REVIEW: Treatment with trastuzumab is a cornerstone of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer treatment, but carries an unfortunate risk of toxicity to the cardiovascular system. Here we review recent findings on trastuzumab-associated cardiotoxicity, focusing on its incidence, diagnosis, and treatment. RECENT FINDINGS: Screening with multigated acquisition scan (MUGA) or echocardiogram (ECHO) is recommended to assess cardiac function prior to and during trastuzumab therapy. Because trastuzumab-induced cardiotoxicity is typically reversible, cessation of trastuzumab and/or administration of first line heart failure agents effectively restores cardiac function in most cases. Severe trastuzumab-induced cardiotoxicity is rare enough that the risk-benefit ratio still weighs in favor of its use in the vast majority of patients with HER2+ breast cancer. SUMMARY: An improved understanding of the pathophysiology underlying trastuzumab-induced cardiotoxicity and the identification of patients at highest risk will allow us to continue to safely administer trastuzumab in patients with breast cancer.

Mediastinal seminoma presenting with superior vena cava syndrome.

We present a rare cause of superior vena cava syndrome (SVC) in a previously healthy male aged 31 years. Malignancy was suspected due to unintentional weight loss and childhood exposure to radioactive fallout from a nuclear facility accident. A very large anterior mediastinal mass was identified and demonstrated to be an extragonadal seminoma. Extragonadal germ cell tumours are rare tumours with a high potential for cardiovascular, pulmonary and vascular sequelae. Studies have documented an increased risk of developing seminoma in patients with radioactive exposure. Chemotherapy was initiated, during which the patient experienced progressive and new symptoms, found to be due to extensive thromboembolic disease, which responded well to anticoagulation. Seventy-two months after completing chemotherapy, without need for surgical management, he remains free of the disease.

Idiopathic granulomatous mastitis: imaging update and review.

OBJECTIVES: The purpose of this study was to review the imaging features of idiopathic granulomatous mastitis (IGM) with clinical and pathology correlation. METHODS: With institutional review board (IRB) approval, a retrospective search of the surgical pathology database from January 2000 to July 2015 was performed. Clinical, imaging and histology findings were reviewed. Cases of granulomatous mastitis without a known source, diagnosed with percutaneous or surgical biopsy, were included in our analysis. RESULTS: Seventeen cases of IGM were identified with imaging available for review. The majority of patients presented with a palpable abnormality, whereas a minority were asymptomatic with an abnormal screening mammogram. At imaging, IGM most often demonstrated a focal asymmetry at mammography, a hypoechoic mass with irregular or angular margins at ultrasound, and robust enhancement with mixed progressive and plateau kinetics at magnetic resonance imaging (MRI). Axillary lymph nodes were reactive in appearance at ultrasound. Molecular breast imaging performed in one case showed mild focal asymmetric radiotracer uptake. CONCLUSION: IGM is a rapidly progressive rare inflammatory condition of the breast resulting in non-necrotizing granuloma formation. Imaging features mimic breast carcinoma and diagnosis can be difficult. Radiologists' awareness of this condition is essential to prevent delayed or unnecessary treatment. TEACHING POINTS: • Idiopathic granulomatous mastitis is rapidly progressive inflammatory condition. • Imaging features may mimic breast carcinoma or infection. • Ultrasound shows irregular hypoechoic masses with increased vascularity and sinus tracts. • MRI shows irregular, enhancing masses or non-mass enhancement with microabscesses. • MRI is useful for assessment of breast involvement and response to treatment.

Malignant Bowel Obstruction in Patients With Recurrent Ovarian Cancer.

We sought to report incidence, risk factors, and survival related to bowel obstruction in 311 ovarian cancer patients with recurrent disease. A total of 68 (22%) had a documented bowel obstruction during their cancer course, and 49 (16%) developed it after cancer recurrence. Surprisingly, 142 (45%) fit into an "unknown" category (3+ months of data lacking from last contact/death). No risk factors were identified; management included surgery (n = 21), conservative measures (n = 21), and other (n = 7). Documented bowel obstruction was not associated with a statistically significant reduction in survival after cancer recurrence. In conclusion, although bowel obstruction occurs in only a subgroup of patients with ovarian cancer and does not appear to detract from survival after cancer recurrence, limited end-of-life information may be resulting in an underestimation of incidence.

Systems biology approaches to adverse drug effects: the example of cardio-oncology.

Increased awareness of the cardiovascular toxic effects of chemotherapy has led to the emergence of cardio-oncology (or onco-cardiology), which focuses on screening, monitoring and treatment of patients with cardiovascular dysfunctions resulting from chemotherapy. Anthracyclines, such as doxorubicin, and HER2 inhibitors, such as trastuzumab, both have cardiotoxic effects. The biological rationale, mechanisms of action and cardiotoxicity profiles of these two classes of drugs, however, are completely different, suggesting that cardiotoxic effects can occur in a range of different ways. Advances in genomics and proteomics have implicated several genomic variants and biological pathways that can influence the susceptibility to cardiotoxicity from these, and other drugs. Established pathways include multidrug resistance proteins, energy utilization pathways, oxidative stress, cytoskeletal regulation and apoptosis. Gene-expression profiles that have revealed perturbed pathways have vastly increased our knowledge of the complex processes involved in crosstalk between tumours and cardiac function. Utilization of mathematical and computational modelling can complement pharmacogenomics and improve individual patient outcomes. Such endeavours should enable identification of variations in cardiotoxicity, particularly in those patients who are at risk of not recovering, even with the institution of cardioprotective therapy. The application of systems biology holds substantial potential to advance our understanding of chemotherapy-induced cardiotoxicity.

Acupuncture in the postoperative setting for breast cancer patients: a feasibility study.

Acupuncture is used to treat a variety of symptoms and conditions associated with cancer and cancer treatments. The present study was performed to evaluate the feasibility of providing acupuncture in the hospital setting for breast cancer patients and to evaluate the short-term effect of acupuncture on stress, anxiety, and pain. This was an open label study conducted at Mayo Clinic Hospital, Methodist and Saint Marys Campus, Rochester, Minnesota. A total of 20 adult breast cancer patients undergoing mastectomy and/or breast reconstruction were recruited and offered daily acupuncture intervention beginning postoperative day 1 and continuing for the duration of the hospital stay. Outcome measures included the Symptom Visual Analog Scale (VAS) and Satisfaction Question and Was-it-Worth-it (WIWI) Questionnaire. It was found that acupuncture is a feasible option for postoperative breast cancer patients. In addition, it can significantly decrease the levels of anxiety (p = 0.0065), tension/muscular discomfort (p < 0.001) and pain (p = 0.023). The association between acupuncture and relaxation was found to be statistically borderline (p = 0.053). This feasibility study showed that acupuncture can be integrated into a busy postsurgical clinical practice. These results also suggest that acupuncture may be an important intervention in the postoperative setting for breast cancer patients.

Medical factors influencing decision making regarding radiation therapy for breast cancer.

Radiation therapy is an important and effective adjuvant therapy for breast cancer. Numerous health conditions may affect medical decisions regarding tolerance of breast radiation therapy. These factors must be considered during the decision-making process after breast-conserving surgery or mastectomy for breast cancer. Here, we review currently available evidence focusing on medical conditions that may affect the patient-provider decision-making process regarding the use of radiation therapy.

Evaluation and management of patients with heart disease and cancer: cardio-oncology.

The care for patients with cancer has advanced greatly over the past decades. A combination of earlier cancer diagnosis and greater use of traditional and new systemic treatments has decreased cancer-related mortality. Effective cancer therapies, however, can result in short- and long-term comorbidities that can decrease the net clinical gain by affecting quality of life and survival. In particular, cardiovascular complications of cancer treatments can have a profound effect on the health of patients with cancer and are more common among those with recognized or unrecognized underlying cardiovascular diseases. A new discipline termed cardio-oncology has thus evolved to address the cardiovascular needs of patients with cancer and optimize their care in a multidisciplinary approach. This review provides a brief introduction and background on this emerging field and then focuses on its practical aspects including cardiovascular risk assessment and prevention before cancer treatment, cardiovascular surveillance and therapy during cancer treatment, and cardiovascular monitoring and management after cancer therapy. The content of this review is based on a literature search of PubMed between January 1, 1960, and February 1, 2014, using the search terms cancer, cardiomyopathy, cardiotoxicity, cardio-oncology, chemotherapy, heart failure, and radiation.

Care of breast cancer survivors after treatment.

More than 200,000 women in the United States will be diagnosed with breast cancer in 2014. It is estimated that by 2022, the number of survivors will climb to nearly 4 million. Breast cancer survivors require regular follow-up care, some of which requires the skills of an oncologist and some of which can be provided by a primary care physician. This article looks at common conditions affecting survivors and discusses ways that oncologists and primary care physicians can work together to best serve this population.