Cardiovascular Disease Amongst Women Treated for Breast Cancer: Traditional Cytotoxic Chemotherapy, Targeted Therapy, and Radiation Therapy.

PURPOSE OF REVIEW: Cardiotoxicity can occur acutely during breast cancer treatment and impact the potential for the intended cancer treatment regime to be completed, or as a late effect affecting cancer survivorship. Indeed, the most common cause of mortality in females with early breast cancer is cardiovascular disease, especially in those over the age of 65. Optimal cancer care therefore needs to be delivered without jeopardising cardiovascular health. Understanding the different cardiotoxicities associated with breast cancer treatment is vital to this approach, and therefore, this article seeks to provide an overview of this. RECENT FINDINGS: Tyrosine kinase inhibitors targeting human epidermal growth factor receptor (HER)-2, immune checkpoint inhibitors (ICI), and cyclin-dependent kinase (CDK) inhibitors are new targeted breast cancer treatments. In particular, ICI are associated with myocarditis that carries a significant mortality, whilst the CDK inhibitor ribociclib causes QT prolongation that requires cardiac surveillance and appropriate dose adjustment to prevent ventricular arrhythmias. The need has always been for strategies to mitigate the risks of cardiovascular toxicities, and new data is promising for the use of dexrazoxane in anthracyclines, and the role of beta blockers and angiotensin converting enzymes inhibitors in anthracyclines and HER-2 monoclonal antibodies such as trastuzumab. Significant headways in breast cancer treatment have resulted in reductions in disease recurrence and mortality, but cardiovascular complications continue to impact the ability to deliver some of these cancer treatments, and the period of cancer survivorship.

Outcomes of the 2019 novel coronavirus in patients with or without a history of cancer: a multi-centre North London experience.

BACKGROUND: This study aims to compare the outcomes of COVID-19-positive disease in patients with a history of cancer to those without. METHODS: We retrospectively collected clinical data and outcomes of COVID-19 positive cancer patients treated consecutively in five North London hospitals (cohort A). Outcomes recorded included time interval between most recent anti-cancer treatment and admission, severe outcome [a composite endpoint of intensive care unit (ITU) admission, ventilation and/or death] and mortality. Outcomes were compared with consecutively admitted COVID-19 positive patients, without a history of cancer (cohort B), treated at the primary centre during the same time period (1 March-30 April 2020). Patients were matched for age, gender and comorbidity. RESULTS: The median age in both cohorts was 74 years, with 67% male, and comprised of 30 patients with cancer, and 90 without (1:3 ratio). For cohort B, 579 patients without a history of cancer and consecutively admitted were screened from the primary London hospital, 105 were COVID-19 positive and 90 were matched and included. Excluding cancer, both cohorts had a median of two comorbidities. The odds ratio (OR) for mortality, comparing patients with cancer to those without, was 1.05 [95% confidence interval (CI) 0.4-2.5], and severe outcome (OR 0.89, 95% CI 0.4-2.0) suggesting no increased risk of death or a severe outcome in patients with cancer. Cancer patients who received systemic treatment within 28 days had an OR for mortality of 4.05 (95% CI 0.68-23.95), p = 0.12. On presentation anaemia, hypokalaemia, hypoalbuminaemia and hypoproteinaemia were identified predominantly in cohort A. Median duration of admission was 8 days for cancer patients and 7 days for non-cancer. CONCLUSION: A diagnosis of cancer does not appear to increase the risk of death or a severe outcome in COVID-19 patients with cancer compared with those without cancer. If a second spike of virus strikes, rational decision making is required to ensure optimal cancer care.

The impact of Oncotype DX breast cancer assay results on clinical practice: a UK experience.

BACKGROUND: Genomic tests are increasingly being used by clinicians when considering adjuvant chemotherapy for patients with oestrogen receptor-positive (ER+), human epidermal growth factor 2-negative (HER2-) breast cancer. The Oncotype DX breast recurrence score assay was the first test available in the UK National Health Service. This study looked at how UK clinicians were interpreting Recurrence Scores (RS) in everyday practice. METHODS: RS, patient and tumour characteristics and adjuvant therapy details were retrospectively collected for 713 patients from 14 UK cancer centres. Risk by RS-pathology-clinical (RSPC) was calculated and compared to the low/intermediate/risk categories, both as originally defined (RS < 18, 18-30 and > 30) and also using redefined boundaries (RS < 11, 11-25 and > 25). RESULTS: 49.8%, 36.2% and 14% of patients were at low (RS < 18), intermediate (RS 18-30) and high (RS > 30) risk of recurrence, respectively. Overall 26.7% received adjuvant chemotherapy. 49.2% of those were RS > 30; 93.3% of patients were RS > 25. Concordance between RS and RSPC improved when intermediate risk was defined as RS 11-25. CONCLUSIONS: This real-world data demonstrate the value of genomic tests in reducing the use of adjuvant chemotherapy in breast cancer. Incorporating clinical characteristics or RSPC scores gives additional prognostic information which may also aid clinicians' decision making.

Quality of life with cediranib in relapsed ovarian cancer: The ICON6 phase 3 randomized clinical trial.

BACKGROUND: The ICON6 trial showed that cediranib, an oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, improved clinical outcomes for patients with platinum-sensitive relapsed ovarian cancer when it was used with chemotherapy and was continued as maintenance therapy. This study describes health-related quality of life (QOL) during the first year of treatment. METHODS: Four hundred fifty-six women were randomly allocated to receive standard chemotherapy only, chemotherapy with concurrent cediranib, or chemotherapy with cediranib administered concurrently and continued as maintenance. Patients completed QOL questionnaires until disease progression every 3 weeks during chemotherapy and then every 6 weeks to 1 year. Patients alive with disease progression completed a QOL form 1 year after randomization. The primary QOL endpoint was the global score from the Quality of Life Questionnaire Core 30 (of the European Organization for Research and Treatment of Cancer) at 1 year, with the standard chemotherapy group compared with the concurrent-maintenance cediranib group. RESULTS: The rate of questionnaire compliance was 90% at the baseline and 76% at 1 year and was similar across the 3 groups. The mean global QOL score at 1 year was 62.6 points for the standard chemotherapy group and 68.7 points for the concurrent-maintenance group (+4.5; 95% confidence interval, -2.0 to 11.0; P = .18). Sensitivity analyses suggested that this finding was robust to the effect of missing data, and the improvement became statistically significant after adjustments for self-reported diarrhea. CONCLUSIONS: The 6th study by the International Collaboration in Ovarian Neoplasm (ICON6) showed a significant improvement in progression-free survival with cediranib as concurrent and maintenance therapy. No QOL detriment with cediranib was found 1 year after treatment was commenced. The maintenance of QOL along with prolonged cancer control suggests that cediranib has a valuable role in the treatment of relapsed ovarian cancer. Cancer 2017;123:2752-61. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial.

BACKGROUND: Angiogenesis is a validated clinical target in advanced epithelial ovarian cancer. Cediranib is an oral antiangiogenic vascular endothelial growth factor receptor 1-3 inhibitor that has shown antitumour activity in recurrent ovarian cancer. We assessed efficacy and safety of cediranib in combination with platinum-based chemotherapy and as continued maintenance treatment in patients with first relapse of platinum-sensitive ovarian cancer. METHODS: In this randomised, three-arm, double-blind, placebo-controlled phase 3 trial, we randomly assigned patients aged 18 years or older with relapsed platinum-sensitive ovarian cancer at 63 centres in Australia, Canada, New Zealand, Spain, and the UK. Participants received up to six cycles of platinum-based chemotherapy (once every 3 weeks) then entered a maintenance phase. Participants were randomly allocated (2:3:3), with five stratification factors and in alternating blocks, to receive placebo alongside chemotherapy and then placebo only maintenance (arm A; reference), cediranib 20 mg once-daily alongside chemotherapy then placebo only maintenance (arm B; concurrent), or cediranib 20 mg once-daily alongside chemotherapy then cediranib 20 mg once-daily maintenance (arm C; maintenance). Patients continued treatment to progression or excessive toxic effects. The primary efficacy endpoint was progression-free survival between arms A and C. Efficacy analysis was by intention to treat. Safety was assessed in all patients who received the allocated study drug. This trial is registered with ClinicalTrials.gov, number NCT00532194; the ISRCTN registry, number ISRCTN68510403; and ANZ Clinical Trials Registry, number ACTRN1261000016003. FINDINGS: We randomly assigned 486 [corrected] women between Nov 13, 2007, and Dec 23, 2011; results presented are for 456 patients randomly assigned subsequent to the 30mg safety phase. During a median of 19·5 months (IQR 14-26) follow-up, 113 (96%) of 118 women assigned to arm A and 141 (86%) of 164 assigned to arm C had disease progression. Median progression-free survival was 11·0 months (95% CI 10·4-11·7) in arm C and 8·7 months (7·7-9·4) in arm A (hazard ratio 0·56, 0·44-0·72, p<0·0001). 156 (90%) of 174 patients in arm B had disease progression, and median progression-free survival was 9·9 months (95% CI 9·4-10·5). Diarrhoea, neutropenia, hypertension, and voice changes were significantly more common, during chemotherapy with cediranib, and diarrhoea, hypothyroidism and voice changes were more common during maintenance. Poor compliance with cediranib was noted during maintenance treatment with toxic effects being the most common cause for discontinuation. INTERPRETATION: Cediranib, when given orally with chemotherapy and continued as maintenance, yielded a meaningful improvement [corrected] in progression-free survival in women with recurrent platinum-sensitive ovarian cancer, albeit with added toxic effects. The positive results in ICON6 could provide women with a new therapeutic option for recurrent ovarian cancer. Assessment of the secondary endpoint of overall survival will need longer follow-up. FUNDING: Medical Research Council, Cancer Research UK, Canadian Cancer Society Research Institute, Cancer Australia, National Gynecological Cancer Centre, and AstraZeneca.

Switching from standard to dose-dense chemotherapy in front-line treatment of advanced ovarian cancer: a retrospective study of feasibility and efficacy.

BACKGROUND: Current standard neoadjuvant treatment for advanced ovarian cancer is 3-weekly platinum-based chemotherapy (CP3w). Patients unable to have interval debulking surgery (IDS) or with significant residual disease have a poor outcome to CP3w treatment. We investigated the outcome in patients who were switched to dose-dense chemotherapy. METHODS: We retrospectively analysed 30 patients treated at UCLH in 2009-2013, who switched to dose-dense chemotherapy after neoadjuvant CP3w, having achieved a poor response/progressed and unable to proceed to IDS (n=21), or had >1 cm residual disease after IDS (n=9). Treatment was 3-weekly carboplatin and weekly paclitaxel (n=23), or both drugs weekly (n=7). For comparison, we included 30 matched patients treated with CP3w followed by IDS (n=24, without or ≤1 cm residual disease; n=6, with >1 cm residual disease). Time to progression (TTP) and overall survival (OS) were measured from the date of diagnosis until progression (CT scan or CA-125) and death from any cause, respectively. RESULTS: Baseline characteristics were similar in both groups. The response rate to dose-dense chemotherapy was 70% (Gynecological Cancer Intergroup criteria). In the dose-dense group, 24 patients had tumour progression and 16 died; the corresponding numbers in the control group were 24 and 11. Median TTP was 15.8 months with dose-dense therapy, higher than expected for this patient group, and the same as in the control group (15.7 months) undergoing IDS, p=0.27. Median TTP in patients with residual disease postsurgery was 16.5 months (dose-dense) and 10.8 months (controls), p=0.02. TTP in dose-dense patients who did not have surgery was 10.4 months. Median OS was 31.3 (dose-dense) and 59.6 months (controls), p=0.06. Dose-dense chemotherapy was well tolerated: only three patients interrupted treatment due to toxicity. CONCLUSION: Switching to dose-dense chemotherapy in patients who failed to respond to CT3w neoadjuvant chemotherapy appears to be an effective strategy and requires further investigation.

Biomarkers in the development of anti-angiogenic therapies for ovarian cancer.

The treatment of ovarian cancer remains challenging as the majority of patients will relapse and die from their disease despite successful first-line treatment. New treatment strategies are needed and recently there has been an explosion of new agents being tested in ovarian cancer. Most of these are directed against molecularly defined pathways and a significant proportion target angiogenesis, an important process in the growth of ovarian cancer. We review the role of angiogenesis in the pathophysiology of ovarian cancer and discuss the development of the most promising anti-angiogenic drugs in this disease, including the first large phase III trials with bevacizumab which have demonstrated a disease-modifying role in ovarian cancer. Other studies with this drug and other inhibitors of the angiogenic pathways are underway in the first-line and recurrent disease settings. The financial cost of these agents, increased toxicity and requirement for prolonged therapy necessitates the urgent need to identify and validate biomarkers to guide the use of these drugs in the future. There are over 200 candidate biomarkers being studied in ovarian cancer. However, currently there are no validated biomarkers to predict response or progression of disease. In this review we present a selection of biomarkers that are under investigation and discuss their benefits and limitations.

Clinical trials and decision-making strategies for optimal treatment of relapsed ovarian cancer.

The proportion of patients with advanced ovarian cancer who relapse has remained high and fairly constant over the last decade. Choosing treatment for recurrent ovarian cancer is complex. Many active therapeutic agents are available, and there are challenges in defining the optimal timing and sequencing of treatments. Furthermore, the explosion in the number of biological agents presents additional challenges in identifying their activity and place in the pathway of treatment. Establishing optimal treatment as monotherapy, or in combination with chemotherapy, or as maintenance treatment requires new approaches to trial design, selecting meaningful endpoints and conducting carefully conducted trials with translational studies. Patients with relapsed ovarian cancer can now survive several years; the aim is to increase this further.

Targeted trials in ovarian cancer.

The last five years has seen a major expansion in the number of clinical trials with molecular targeted agents in ovarian cancer. Most of the studies are with anti-angiogenic agents. This review discusses the rationale for molecular targeted therapy in ovarian cancer and the current randomized trials. It focuses on anti-angiogenic agents, particularly bevacizumab and small molecule VEGFR tyrosine kinase inhibitors, and EGFR, α-folate receptor, PARP, src kinase and IGFR inhibitors. The results of first-line trials and studies in recurrent disease with bevacizumab will soon be available. Results of many other trials with molecular targeted therapy will follow over the next 2-3 years. We highlight some of the complex issues about sequencing, duration of therapy and selection of agents to aid the debate about the best use of molecular targeted agents in the treatment of ovarian cancer.