ESR1 mutations: Moving towards guiding treatment decision-making in metastatic breast cancer patients

Mutations in the gene coding for the estrogen receptor (ER), ESR1, have been associated with acquired endocrine resistance in patients with ER-positive metastatic breast cancer (MBC). Functional studies revealed that these ESR1 mutations lead to constitutive activity of the ER, meaning that the receptor is active in absence of its ligand estrogen, conferring resistance against several endocrine agents. While recent clinical studies reported that the occurrence of ESR1 mutations is rare in primary breast cancer tumors, these mutations are more frequently observed in metastatic tissue and circulating cell-free DNA of MBC patients pretreated with endocrine therapy. Given the assumed impact that the presence of ESR1 mutations has on outcome to endocrine therapy, assessing ESR1 mutations in MBC patients is likely to be of significant interest to further individualize treatment for MBC patients. Here, ESR1 mutation detection methods and the most relevant pre-clinical and clinical studies on ESR1 mutations regarding endocrine resistance are reviewed, with particular interest in the ultimate goal of guiding treatment decision-making based on ESR1 mutations

Toxicity of (neo)adjuvant chemotherapy for BRCA1- and BRCA2-associated breast cancer

Treatment with (neo)adjuvant chemotherapy for breast cancer, as currently given, causes cell damage by induction of double-strand DNA breaks. Because BRCA1 and BRCA2 proteins play a role in the repair of DNA damage, the efficacy of (neo)adjuvant chemotherapy may be increased in BRCA1/2-associated breast cancer patients. As a downside, acute chemotherapy-related toxicity may also be increased. We selected all female patients who were treated at the Erasmus MC Cancer Institute, with (neo)adjuvant chemotherapy for primary or locoregional recurrence of breast cancer (PBC/LR) between January 1, 2004 and December 31, 2014. The primary outcome was the relative total dose intensity (RTDI), calculated for anthracyclines and taxanes separately. Secondary outcomes were the occurrence of febrile neutropenia, delay in chemotherapy administration, and switch to another chemotherapy regimen due to toxicity. In total, 701 patients treated for PBC/LR were eligible for data analyses, among which 85 BRCA1/2 mutation carriers (n = 67 BRCA1 and n = 18 BRCA2). The mean RTDI for anthracyclines was not significantly different between both groups (98.7 % in the BRCA1/2, 96.6 % in the sporadic group, p = 0.27). Also the mean RTDI for taxanes was not significantly different between the groups (93.6 % in the BRCA1/2-associated, 90.0 % in the sporadic group, p = 0.12). Linear regression analysis revealed no significant effect of BRCA1/2 mutation carriership on the RTDIs. No significant differences were found in the percentages of patients presenting with febrile neutropenia, having a delay in chemotherapy administration or switching to an altered chemotherapy regimen. Additionally, the odds ratios showed no significant effect of BRCA1/2 mutation carriership on the secondary outcome variables. (Neo)adjuvant chemotherapy-related toxicity was not different between BRCA1/2-associated and sporadic breast cancer patients suggesting that the DNA damage repair mechanism of non-cancer cells with only one normal copy of either the BRCA1 or BRCA2 gene is sufficiently functional to handle acute chemotherapy-associated toxicity

Homologous recombination deficiency testing for brca-like tumors: The road to clinical validation

Germline BRCA mutations result in homologous recombination deficiency (HRD) in hereditary breast and ovarian cancer, as well as several types of sporadic tumors. The HRD phenotype makes these tumors sensitive to DNA double strand break-inducing agents, including poly-(ADPribose)-polymerase (PARP) inhibitors. Interestingly, a subgroup of cancers without a BRCA mutation also shows an HRD phenotype. Various methods for selecting patients with HRD tumors beyond BRCA-mutations have been explored. These methods are mainly based on DNA sequencing or functional characteristics of the tumor. We here discuss the various tests and the status of their clinical validation

The effect of immediate breast reconstruction on the timing of adjuvant chemotherapy: a systematic review

Adjuvant chemotherapy is often needed to achieve adequate breast cancer control. The increasing popularity of immediate breast reconstruction (IBR) raises concerns that this procedure may delay the time to adjuvant chemotherapy (TTC), which may negatively impact oncological outcome. The current systematic review aims to investigate this effect. During October 2014, a systematic search for clinical studies was performed in six databases with keywords related to breast reconstruction and chemotherapy. Eligible studies met the following inclusion criteria: (1) research population consisted of women receiving therapeutic mastectomy, (2) comparison of IBR with mastectomy only groups, (3) TTC was clearly presented and mentioned as outcome measure, and (4) original studies only (e.g., cohort study, randomized controlled trial, case–control). Fourteen studies were included, representing 5270 patients who had received adjuvant chemotherapy, of whom 1942 had undergone IBR and 3328 mastectomy only. One study found a significantly shorter mean TTC of 12.6 days after IBR, four studies found a significant delay after IBR averaging 6.6–16.8 days, seven studies found no significant difference in TTC between IBR and mastectomy only, and two studies did not perform statistical analyses for comparison. In studies that measured TTC from surgery, mean TTC varied from 29 to 61 days for IBR and from 21 to 60 days for mastectomy only. This systematic review of the current literature showed that IBR does not necessarily delay the start of adjuvant chemotherapy to a clinically relevant extent, suggesting that in general IBR is a valid option for non-metastatic breast cancer patients

Omitting re-excision for focally positive margins after breast-conserving surgery does not impair disease-free and overall survival

Purpose: In contrast to other countries, the Dutch breast cancer guideline does not recommend re-excision for focally positive margins after breast-conserving surgery (BCS) in invasive tumor and does recommend whole-breast irradiation including boost. We investigated whether omitting re-excision as compared to performing re-excision affects prognosis with a retrospective population-based cohort study. Methods: The total cohort included 32,119 women with primary BCS for T1–T3 breast cancer diagnosed between 2003 and 2008 from the nationwide Netherlands cancer registry. The subcohort included 10,433 patients in whom the resection margins were registered. Outcome measures were 5-year ipsilateral breast tumor recurrence (IBTR) rate, 5-year disease-free survival (DFS) rate, and 10-year overall survival (OS) rate. Results: In the total cohort, 25,878 (80.6%) did not have re-excision, 2368 (7.4%) had re-excision by BCS, and 3873 (12.1%) had re-excision by mastectomy. Five-year IBTR rates were 2.1, 2.8, and 2.9%, respectively (p = 0.001). In the subcohort, 7820 (75.0%) had negative margins without re-excision, 492 (4.7%) had focally positive margins without re-excision, 586 (5.6%) had focally positive margins and underwent re-excision, and 1535 (14.7%) had extensively positive margins and underwent re-excision. Five-year IBTR rate was 2.3, 2.9, 1.1, and 2.9%, respectively (p = 0.099). Compared to omitting re-excision, performing re-excision for focally positive margins was associated with lower risk of IBTR (adjusted HR 0.30, 95% CI 0.11–0.82), but not with DFS (adjusted HR 0.83 95% CI 0.59–1.17) nor with OS (adjusted HR 1.17 95% CI 0.87–1.59). Conclusion: Omitting re-excision in breast cancer patients for focally positive margins after BCS does not impair DFS and OS, provided that whole-breast irradiation including boost is given

The impact of menstruation persistence or recovery after chemotherapy on survival in young patients with hormone receptor negative breast cancer

Introduction: Hormone replacement therapy can diminish hormone depletion-related complaints in postmenopausal women, but is contraindicated for postmenopausal breast cancer (BC) patients. Recovery of menstruation after chemotherapy-induced amenorrhea in young hormone receptor-negative BC patients however, is accepted. To determine the safety of this strategy, we investigated the effect of recovery of menstruation on disease-free survival (DFS) and overall survival (OS) in young hormone receptor-negative BC patients treated with (neo)adjuvant chemotherapy. Methods: We selected 636 patients from a single-center cohort with early stage hormone receptornegative BC and under the age of 50 years when treated with chemotherapy. Sufficient data on course of menstruation in medical records was retrospectively found for 397 patients, of whom 299 patients (75%) had a recovery of menstruation after chemotherapy. We used Cox proportional hazards models to estimate hazard ratios (HR) for the effect of recovery of menstruation on DFS and OS. Results: Patients with recovery of menstruation after chemotherapy less frequ

Inflammation and fatigue dimensions in advanced cancer patients and cancer survivors: An explorative study

BACKGROUND: Inflammation may underlie cancer-related fatigue; however, there are no studies that assess the relation between fatigue and cytokine

Hospital-based or home-based administration of oncology drugs? A micro-costing study comparing healthcare and societal costs of hospital-based and home-based subcutaneous administration of trastuzumab

Objective: To investigate resource use and time investments of healthcare professionals, patients and their family and to compare healthcare and societal costs of one single hospital-based and one single home-based subcutaneous administration of trastuzumab in The Netherlands. Method: We conducted a bottom-up micro-costing study. Patients diagnosed with HER2+ early or metastatic breast cancer were recruited in four Dutch hospitals. For healthcare costs, data were collected on drug use, consumables, use of healthcare facilities, time of healthcare professionals, and travelling distance of the nurse. For societal costs, data were collected on patient and family costs (including travelling expenses and time of informal caregivers) and productivity losses of paid and unpaid work. Results: Societal costs of one single administration of SC trastuzumab were €1753 within the home-based and €1724 within the hospital-based setting. Drug costs of trastuzumab were identical in both settings (€1651). Healthcare costs were higher for home-based administration (€91 versus €47) mainly because of more time of healthcare professionals (110 versus 38 minutes). Costs for patient and family were, however, lower for home-based administration due to travelling expenses (€7 versus €0) and time of informal caregivers (€14 versus €4). Costs for productivity losses were similar for both settings. Conclusions: Home-based subcutaneous administration of trastuzumab is more time consuming for healthcare professionals and therefore more costly than hospital-based administration. The total budget impact can be large considering that a large number of patients receive a large number of cycles of oncology treatments. If home-based administration is the way forward, novel approaches are crucial for ensuring efficiency of home-based care

From Multiple Quality Indicators of Breast Cancer Care Toward Hospital Variation of a Summary Measure

Objectives: To improve quality in breast cancer care, large numbers of quality indicators are collected per hospital, but benchmarking remains complex. We aimed to assess the validity of indicators, develop a textbook outcome summary measure, and compare case-mix adjusted hospital performance. Methods: From a nationwide population-based registry, all 79 690 nonmetastatic breast cancer patients surgically treated between 2011 and 2016 in 91 hospitals in The Netherlands were included. Twenty-one indicators were calculated and their construct validity tested by Spearman's rho. Between-hospital variation was expressed by interquartile range (IQR), and all valid indicators were included in the summary measure. Standardized scores (observed/expected based on case mix) were calculated as above (>100) or below (<100) expected. The textbook outcome was presented as a continuous and all-or-none score. Results: The size of between-hospital variation varied between indicators. Sixteen (76%) of 21 quality indicators showed construct validity, and 13 were included in the summary measure after excluding redundant indicators that showed collinearity with others owing to strong construct validity. The median all-or-none textbook outcome score was 49% (IQR 42%-54%) before and 49% (IQR 48%-51%) after case-mix adjustment. From the total of 91 hospitals, 3 hospitals were positive (3%) and 9 (10%) were negative outlier

Extent of ductal carcinoma in situ according to breast cancer subtypes: a population-based cohort study

textabstractDuctal carcinoma in situ (DCIS) is a precursor of invasive breast carcinoma (IBC). The DCIS component is often more extensive than the invasive component, which affects local control. The aim of our study was to analyze features of DCIS within different IBC subtypes, which may contribute to the optimization of personalized approaches for patients with IBC. Patients with IBC reported according to the synoptic reporting module in the Netherlands between 2009 and 2015 were included. Data extraction included characteristics of the invasive component and, if present, several features of the DCIS component. Resection margin status analyses were restricted to patients undergoing breast-conserving surgery (BCS). Differences between subtypes were tested by a Chi-square test, spearman’s Rho test or a one-way ANOVA test. Overall, 36.937 cases of IBC were included. About half of the IBCs (n = 16.014; 43.4 %) were associated with DCIS. Her2+ IBC (irrespective of ER status) was associated with a higher prevalence of adjacent DCIS, a larger extent of DCIS and a higher rate of irradicality of the DCIS component as compared to ER+/Her2− and triple-negative subtypes (P < 0.0001 for all variables). The prevalence of DCIS in triple-negative IBC on the other hand was lowest. In this large population-based cohort study, we showed significant differences between the prevalence and extent of DCIS according to IBC subtypes, which is also reflected in the resection margin status in patients treated with BCS. Our data provide important information regarding the optimization of local therapy according to IBC subtypes