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Purpose: Adverse events (AE) during oncology clinical trials are typically reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), which provides information about the frequency and severity of AEs from the provider's perspective. Instruments that track patient-reported outcomes (PRO) complement the CTCAE and provide additional patient-centered information about the toxicity profile of an anti-cancer drug., Methods: We conducted a single-arm, open-label phase II study of eribulin as first- or second-line therapy for metastatic hormone receptor-positive/HER2-negative (HR+/HER2-) or triple-negative breast cancer (TNBC). Patients were recruited simultaneously into each cohort by tumor subtype. The primary endpoint was overall response rate (ORR). Secondary endpoints included evaluation of toxicity by CTCAE and PRO instruments and agreement between CTCAE and PRO. The study also investigated single-nucleotide polymorphisms (SNPs) associated with treatment-induced neurotoxicity., Results: 83 patients were enrolled: 45 into the HR+/HER2- cohort and 38 into the TNBC cohort. The ORR was 35.6% (90% CI 24-39%) in the HR+/HER2- cohort and 13.2% (90% CI 5-26%) in the TNBC cohort. Stable disease as the best response was recorded in 55.1% of patients with HR+/HER2- disease and 60.5% with TNBC. Toxicity analysis revealed a discordance between CTCAE and PRO assessment in many patients, with a focus on fatigue, alopecia, and neuropathy. Pharmacogenomic analysis identified SNPs associated with treatment-induced peripheral neuropathy., Conclusions: Eribulin is active in HER2- breast cancer. This study reveals that provider-assessed AEs can vary greatly from patient experiences. Future studies should incorporate CTCAE and PRO instruments to improve reporting of treatment-related AEs. ClinicalTrials.gov Registration: NCT01827787.

The incidence of breast cancer diagnosed during pregnancy is increasing. We sought to characterize patient, treatment, pregnancy and lactation factors among young women with newly diagnosed breast cancer during pregnancy in a prospective cohort study. We identified all women who were pregnant when diagnosed with invasive breast cancer among those enrolled in the Young Women's Breast Cancer Study (NCT01468246), and collected details on pregnancy, birth and lactation from surveys, and treatment information medical record review. Of 1302 enrolled participants, 976 women with invasive breast cancer completed full baseline surveys, among whom 39 (4.0%) patients reported being pregnant at diagnosis. Median age at diagnosis was 34 years (range: 25-40), with stage distribution: I, 28%; II, 44%; III, 23%; and IV, 5%. 74% of patients (29/39) had grade 3 tumors, 59% (23/39) ER-positive, and 31% (12/39) HER2-positive disease. 23 (59%) had surgery during pregnancy, 4 (17%) during the first trimester. Among the women who had surgery during pregnancy, 61% (14/23) underwent lumpectomy, 35% (8/23) unilateral, and 4% (1/23) bilateral mastectomy. All patients who had chemotherapy (51%, 20/39) received it in second and third trimesters, and had ACx4. There were 31 live births, 2 spontaneous, and 5 therapeutic abortions. Among live births, 16 (41%) were before 37 weeks of gestation. Three women reported breastfeeding. Within 6 months after delivery, comprehensive staging in 13 patients showed upstaging in four patients. In a contemporary cohort of young women with breast cancer, pregnancy at diagnosis is relatively uncommon. Treatment during pregnancy can generally be consistent with standard surgical and chemotherapy approaches, with attention to timing of therapies. Longer-term outcomes including effects of some timing issues including delayed use of anti-HER2 therapy on patient outcomes warrant further research., (© 2019 Wiley Periodicals, Inc.)

Purpose: The identification of patients with metastatic triple-negative breast cancer (mTNBC) who are expected to benefit from platinum-based chemotherapy is of interest. We conducted a single-arm phase II clinical trial of single-agent platinum for mTNBC with biomarker correlates., Patients and Methods: Patients with mTNBC received first- or second-line cisplatin (75 mg/m(2)) or carboplatin (area under the concentration-time curve 6) by physician's choice once every 3 weeks. Coprimary end points were objective response rate (RR) and response prediction by p63/p73 gene expression. Secondary and exploratory end points included toxicity assessment, RR in cisplatin versus carboplatin, and RR in molecularly defined subgroups, including BRCA1/2 mutation carriers., Results: Patients (N = 86; 69 as first-line therapy) received cisplatin (n = 43) or carboplatin (n = 43). RR was 25.6% (95% CI, 16.8% to 36%) and was numerically higher with cisplatin (32.6%) than with carboplatin (18.7%). RR was 54.5% in patients with germline BRCA1/2 mutations (n = 11). In patients without BRCA1/2 mutations (n = 66), exploratory analyses showed that a BRCA-like genomic instability signature (n = 32) discriminated responding and nonresponding tumors (mean homologous recombination deficiency-loss of heterozygosity/homologous recombination deficiency-large-scale state transitions [HRD-LOH/HRD-LST] scores were 12.68 and 5.11, respectively), whereas predefined analysis by p63/p73 expression status (n = 61), p53 and PIK3CA mutation status (n = 53), or PAM50 gene expression subtype (n = 55) did not. Five of the six long-term responders alive at a median of 4.5 years lacked germline BRCA1/2 mutations, and two of them had increased tumor HRD-LOH/HRD-LST scores., Conclusion: Platinum agents are active in mTNBC, especially in patients with germline BRCA1/2 mutations. A measure of tumor DNA repair function may identify patients without mutations who could benefit from platinum therapy agents. Prospective controlled confirmatory trials are warranted., (© 2015 by American Society of Clinical Oncology.)

Dysregulation of the cell cycle is a classic hallmark of cancer growth and metastatic potential. Re-establishing cell cycle control through CDK inhibition has emerged as an attractive option in the development of targeted cancer therapy. Three oral agents selectively targeting CDK4/6 have been developed: palbociclib, abemaciclib, and LEE011. Preclinical models show optimal activity in hormone receptor positive breast cancer, which may display biologic features suggesting particular dependence on the CDK4/cyclin D1/Rb interaction. Palbociclib has been studied in a randomized phase 2 clinical trial in metastatic hormone receptor positive breast cancer in which the combination of palbociclib and endocrine therapy significantly prolonged progression-free survival over endocrine therapy alone. The toxicity profile of palbociclib and the other CDK 4/6 inhibitors in early phase I and II trials has been predominantly hematologic, characterized by limited neutropenia, as well as variable gastrointestinal toxicity. Multiple phase II and III studies are ongoing with all three agents, and are designed to explore the role of CDK 4/6 inhibition in metastatic hormone receptor positive breast cancer. The next wave of studies will examine further clinical and scientific topics, including the role of CDK 4/6 inhibition in the neo/adjuvant setting, the combination of CDK 4/6 inhibitors with other targeted therapies, and the activity of CDK 4/6 inhibitors in the HER2 positive subset of breast cancer, as well as in other cancer subtypes. Should ongoing study confirm benefits and tolerability of CDK 4/6 inhibition, combination therapy with endocrine agents may become a new standard of care for hormone receptor positive breast cancer.

Brain metastases are common in patients with advanced, Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer. We evaluated the maximum tolerated dose (MTD) and feasibility of lapatinib given concurrently with whole brain radiotherapy (WBRT). Eligible patients had (HER2)-positive breast cancer and ≥1 brain metastasis. Patients received lapatinib 750 mg twice on day one followed by 1000, 1250, or 1500 mg once daily. WBRT (37.5 Gy, 15 fractions) began 1-8 days after starting lapatinib. Lapatinib was continued through WBRT. Following WBRT, patients received trastuzumab 2 mg/kg weekly and lapatinib 1000 mg once daily. The regimen would be considered feasible if <3/27 pts treated at the MTD experienced a dose-limiting toxicity (DLT). Thirty-five patients were enrolled; 17 % had central nervous disease (CNS) only. During dose escalation, no patients receiving 1,000 or 1,250 mg and two of five patients receiving 1,500 mg experienced DLTs (grade 3 mucositis and rash). Overall, 7/27 patients at 1,250 mg (MTD) had DLTs: grade 3 rash (n = 2), diarrhea (n = 2), hypoxia (n = 1), and grade 4 pulmonary embolus (n = 2). Among 28 evaluable patients, the CNS objective response rate (ORR) was 79 % [95% confidence interval (CI) 59-92 %] by pre-specified volumetric criteria; 46 % remained progression-free (CNS or non-CNS) at 6 months. The study did not meet the pre-defined criteria for feasibility because of toxicity, although the relationship between study treatment and some DLTs was uncertain. Given the high ORR, concurrent lapatinib-WBRT could still be considered for future study with careful safety monitoring.

Adjuvant chemotherapy continues to play an important role in breast cancer management. Exposure to chemotherapy can lead to a variety of early and late long-term toxicities, including ovarian failure (with resultant infertility and sexual dysfunction), bone loss, weight gain, neurotoxicity, neurocognitive changes, cardiac toxicity and secondary malignancy. Although chemotherapy effects may vary in medical severity, all effects have the potential to lead to a decrease in quality of life and a decrement on overall health status. Improved understanding of the etiology and management of chemotherapy-related toxicity may allow optimization of patient selection for treatment and ameliorate the concerns of patients who are considering embarking on a chemotherapy program. This article presents an overview of relevant early and late long-term toxicities, with a focus on recent advances and clinical management.

Purpose: Bevacizumab is a treatment option in patients with metastatic breast cancer. Congestive heart failure (CHF) has been reported, although the overall incidence and relative risk (RR) of this complication remains unclear. We performed an up-to-date, comprehensive meta-analysis to determine the risk of serious CHF in patients with breast cancer receiving bevacizumab., Methods: The databases of Medline were searched for articles from 1966 to March 2010. Abstracts presented at the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium meetings were also searched for relevant clinical trials. Eligible studies include randomized trials with bevacizumab in patients with breast cancer. Adequate reporting of safety profile data was required for inclusion. Statistical analyses were conducted to calculate the summary incidence, RR, and 95% CIs by using random-effects models., Results: A total of 3,784 patients were included. Overall incidence results for high-grade CHF in bevacizumab- and placebo-treated patients were 1.6% (95% CI, 1.0% to 2.6%) and 0.4% (95% CI, 0.2% to 1.0%), respectively. The RR of CHF in bevacizumab-treated patients was 4.74 (95% CI, 1.66 to 11.18; P = .001) compared with placebo-treated ones. In subgroup analyses, there were no significant differences in CHF incidence or risk between patients treated with low-dose (2.5 mg/kg) versus high-dose (5 mg/kg) bevacizumab or among patients treated with different chemotherapy regimens. No evidence of publication bias was observed., Conclusion: This is the first comprehensive report to show that bevacizumab is associated with an increased risk of significant heart failure in patients with breast cancer.

Cardiovascular toxicity is a potential short- or long-term complication of anticancer therapy. Exposure to chemotherapy medications, primarily the anthracycline class, can lead to potentially irreversible clinically significant cardiac dysfunction. The advent of novel biologic agents, including monoclonal antibodies and tyrosine kinase inhibitors, has revolutionized the treatment of several types of malignancies. Although targeted therapies are considered less toxic and better tolerated by patients compared with classic chemotherapy agents, rare serious complications have been observed; and longer-term follow-up is needed to determine the exact profile of related cardiac adverse effects. Cardiac toxicity associated with cancer therapies can range from asymptomatic subclinical abnormalities, including electrocardiographic changes and temporary left ventricular ejection fraction decline, to life-threatening events such as congestive heart failure or acute coronary syndromes. Assessment of the prevalence, type, and severity of cardiac toxicity caused by various cancer treatments is a critical topic for patient management and specifically for new drug development. Guidelines for monitoring cardiac adverse effects have been formulated; however, appropriate supportive evidence remains limited. Given the rate of new drug development designed to fulfill unmet oncologic needs, efforts are needed to promote strategies for cardiac risk detection and management and to avoid unintended consequences potentially impeding development of, regulatory approval for, and patient access to novel therapies. These advances require ongoing research to assess and manage the cardiovascular safety of patients treated with anticancer agents, as well as a well-organized collaboration between oncologists and cardiologists. The aim of this review is to summarize potential cardiovascular toxicities for a range of cancer chemotherapeutics and to review general mechanisms of cardiovascular toxicity for each agent., (Copyright 2010 Elsevier Inc. All rights reserved.)

Cytotoxic chemotherapy is a mainstay of treatment for advanced breast cancer. Treatment of metastatic (also called stage IV, advanced, or recurrent) breast cancer is not considered curative. Rather, the goals of treatment with chemotherapy are to prolong survival, alleviate or prevent tumor-related symptoms or complications, and improve quality of life. While the purpose of chemotherapy is to prevent or alleviate symptoms, chemotherapy paradoxically carries considerable toxicities that cause substantial symptoms in patients, notoriously including fatigue, nausea, vomiting, diarrhea, hair loss, mucositis, neutropenia, and neuropathy. Balancing the benefits and the side effects of chemotherapy is further complicated by the natural history of advanced breast cancer, which can be quite prolonged and typically involves multiple lines of chemotherapy, especially in patients whose tumors respond to treatment.

New biological therapies continue to emerge in breast cancer. Recent advances with anti-angiogenesis therapies and anti-HER2 therapies highlight the next generation of treatments that will be entering clinical practice. Important questions regarding these targeted treatments remain, however. There are uncertainties as to how best to integrate new drugs into existing treatment algorithms, whether to use monotherapy or combination therapy with chemotherapy, and how to manage novel side effects seen with these agents. This review highlights recent advances with the anti-vascular endothelial growth factor antibody, bevacizumab, and the dual kinase inhibitor, lapatinib, in the treatment of metastatic breast cancer.

Background: Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer.Methods: PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II-III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1-21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30).Findings: Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9-29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2-90·6) for palbociclib plus endocrine therapy and 88·5% (85·8-90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76-1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3-4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths.Interpretation: At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing.Funding: Pfizer. [ABSTRACT FROM AUTHOR]

The article discusses the use of adjuvant tamoxifen and aromatase inhibitors in treating postmenopausal breast cancer. Topics covered include the benefits of patients from aromatase inhibitors. Also mentioned is the disadvantage of using tamoxifen than aromatase inhibitor treatments and other medications for breast cancer.

Overall survival (OS) is a universally accepted measure of clinical benefit; however, prolonged follow-up is needed to observe sufficient events. Disease-free survival (DFS) has been widely adopted as a primary endpoint for early breast cancer (EBC) trials, as follow-up is comparatively shorter. Here, we present an analysis evaluating DFS as a surrogate for OS for adjuvant treatment of hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) EBC. A systematic literature review which included randomized controlled trials (RCTs) with ≥80% of adult patients with HR+/HER2– EBC was conducted. The RCTs evaluated various systemic therapeutic categories; key inclusion criteria included reporting of DFS and OS hazard ratios (HRs) and mature OS data. Spearman rank correlation and weighted linear regression analyses evaluated DFS and OS HR correlation. A scenario analysis tested base-case analysis robustness, and a parallel analysis using patient-level data was conducted. The base case (N = 14 RCTs) showed an unweighted Spearman coefficient of 0.81 between OS and DFS (weighted: 0.81), with 84% of the variability in OS explained by DFS differences (R 2 from weighted regression). The surrogate threshold effect (Burzykowski T, Buyse M. Pharm Stat. 2006;5:173–186) was 0.82 for DFS/OS HR. Scenario analysis (n = 9 RCTs), which excluded chemotherapy trials, and patient-level analysis using FACE trial data were consistent with the base-case analysis. These analyses support DFS as a reliable surrogate endpoint for OS in adjuvant HR+/HER2− EBC trials. Using DFS as a surrogate measure will permit timelier access to novel treatments for patients with HR+/HER2− EBC. • Validation is needed for DFS as a surrogate for OS in adjuvant HR+/HER2– EBC • DFS and OS were analyzed in RCTs identified from a systematic literature review • Spearman coefficient for DFS/OS was 0.81 (weighted and unweighted) • Weighted regression analysis showed 84% of variability in OS was explained by DFS • These results support DFS as a surrogate for OS in adjuvant HR+/HER2– EBC trials [ABSTRACT FROM AUTHOR]