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Background: Despite histological and molecular differences between invasive lobular carcinoma (ILC) and invasive carcinoma of no special type, according to national treatment guidelines no distinction is made regarding the use of (neo)adjuvant chemotherapy. Studies on the long-term outcome of chemotherapy in patients with ILC are scarce and show inconclusive results., Methods: All patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative ILC with an indication for chemotherapy treated with adjuvant endocrine therapy were selected from the Erasmus Medical Center Breast Cancer database. Cox proportional hazards models were used to estimate the effect of chemotherapy on recurrence-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS)., Results: A total of 520 patients were selected, of whom 379 were treated with chemotherapy and 141 were not. Patients in the chemotherapy group were younger (51 vs. 61 years old; p < .001), had a higher T status (T3+, 33% vs. 14%; p < .001), and more often had lymph node involvement (80% vs. 49%; p < .001) in comparison to the no-chemotherapy group. After adjusting for confounders, chemotherapy treatment was not associated with better RFS (hazard ratio [HR], 1.20; 95% confidence interval [CI], 0.63-2.31), BCSS (HR, 1.24; 95% CI, 0.60-2.58), or OS (HR, 0.97; 95% CI, 0.56-1.66). This was also reflected by adjusted Cox survival curves in the chemotherapy versus no-chemotherapy group for RFS (75% vs. 79%), BCSS (80% vs. 84%), and OS (72% vs. 71%)., Conclusions: Chemotherapy is not associated with improved RFS, BCSS, or OS for patients with ER+/HER2- ILC treated with adjuvant endocrine therapy and with an indication for chemotherapy., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Maintaining functional status is among the most important patient-centered outcomes for older adults with cancer. This study investigated the association between comprehensive geriatric assessment (CGA) and progressive disease or decline of IADL-independence 1 year after chemotherapy, overall survival (OS), and premature termination of chemotherapy. CGA-based functional status and quality of life (QOL) 1 year after chemotherapy are also described., Methods: This prospective cohort study involved patients aged ≥65 years treated with chemotherapy for any cancer type. CGA and the G8-screening tool were performed before and after the completion of chemotherapy. Analyses were adjusted for tumor type and treatment intent: (a) indolent hematological malignancies, (b) aggressive hematological malignancies, c) solid malignancies treated with curative intent, and (d) solid malignancies treated with palliative intent., Results: All 291 included patients lived in The Netherlands; 193 (67.4%) lived fully independent prior to chemotherapy. The median age was 72 years; 164 (56.4%) were male. IADL independence, CGA-based functional status, and QOL were maintained in half of the patients 1 year after chemotherapy. An abnormal G8-score before chemotherapy was a higher risk for progressive disease or a decline of IADL-independence (OR 3.60, 95% CI, 1.98-6.54, P < .0001), prematurely terminated chemotherapy (OR 2.12, 95% CI, 1.24-3.65, P = .006), and shorter median OS (HR 1.71, 95% CI, 1.16-2.52, P = .007). The impact of an abnormal G8-score differed across tumor type (oncological or hematological) and treatment indication (adjuvant or palliative)., Conclusion: An abnormal G8 score before chemotherapy is associated with progressive disease and functional decline after chemotherapy and shorter median OS, especially in patients with solid malignancies., (© The Author(s) 2022. Published by Oxford University Press.)

We investigated the effect of trastuzumab on cardiac function in a real-world historic cohort of patients with HER2-positive metastatic breast cancer (MBC) with reduced baseline left ventricular ejection fraction (LVEF). Thirty-seven patients with HER2-positive MBC and baseline LVEF of 40% to 49% were included. Median LVEF was 46% (interquartile range [IQR] 44%-48%) and median follow-up was 18 months (IQR 9-34 months). During this period, the LVEF did not worsen in 24/37 (65%) patients, while 13/37 (35%) patients developed severe cardiotoxicity defined as LVEF <40% with median time to severe cardiotoxicity of 7 months (IQR 4-10 months) after beginning trastuzumab. Severe cardiotoxicity was reversible (defined as LVEF increase to a value <5%-points below baseline value) in 7/13 (54%) patients, partly reversible (defined as absolute LVEF increase ≥10%-points from nadir to a value >5%-points below baseline) in 3/13 (23%) patients and irreversible (defined as absolute LVEF increase <10%-points from nadir and to a value >5%-points below baseline) in 3/13 (23%) patients. Likelihood of reversibility was numerically higher in patients who received cardio-protective medications (CPM), including ACE-inhibitors, beta-blockers and angiotensine-2 inhibitors, compared to those who did not receive any CPM (71% vs 13%, P = .091). Sixty-five percent of patients who received trastuzumab for HER2-positive MBC did not develop severe cardiotoxicity during a median follow-up of 18 months, despite having a compromised baseline LVEF. If severe cardiotoxicity occurred, it was at least partly reversible in more than two-thirds of the cases. Risks and benefits of trastuzumab use should be balanced carefully in this vulnerable population., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: We aimed to study the predictive value of early two-dimensional echocardiography (2DE) speckle tracking (ST) for left ventricular ejection fraction (LVEF) changes during trastuzumab treatment for HER2-positive breast cancer., Methods: HER2-positive breast cancer patients receiving trastuzumab, with or without anthracycline, underwent 2DE-ST at baseline and after 3 and 6 months (m) trastuzumab. Cardiac magnetic resonance (CMR) imaging (with ST) was performed at baseline and 6 m. We studied the correlation between 2DE-ST- and CMR-derived global longitudinal strain (GLS) and global radial strain (GRS) measured at the same time. Additionally, we associated baseline and 3 m 2DE-ST measurements with later CMR-LVEF, and with cardiotoxicity, defined as CMR-LVEF < 45% and/or absolute decline > 10% during trastuzumab., Results: Forty-seven patients were included. Median baseline LVEF was 60.4%. GLS measurements based on 2DE-ST and CMR showed weak correlation (Pearson's r = 0.33; p = 0.041); GRS measurements were uncorrelated (r = 0.09; p = 0.979). 2DE-LVEF at baseline and 3 m, and 2DE-ST-GLS at 3 m were predictive of CMR-LVEF at 6 m. In contrast, the change in 2DE-ST-GLS at 3 m was predictive of the change in CMR-LVEF at 6 m, whereas the change in 2DE-LVEF was not. Importantly, the 11 patients who developed cardiotoxicity (28%) had larger 2DE-ST-GLS change at 3 m than those who did not (median 5.2%-points versus 1.7%-points; odds ratio for 1% difference change 1.81, 95% confidence interval 1.11-2.93; p = 0.016; explained variance 0.34)., Conclusions: Correlations between 2DE-ST and CMR-derived measurements are weak. Nevertheless, ST-measurements appeared useful to improve the performance of 2DE in predicting LVEF changes after 6 m of trastuzumab treatment., (© 2021. The Author(s).)

Purpose: Patients with HER2-positive metastatic breast cancer (MBC) usually receive many years of trastuzumab treatment. It is unknown whether these patients require continuous left ventricular ejection fraction (LVEF) monitoring. We studied a real-world cohort to identify risk factors for cardiotoxicity to select patients in whom LVEF monitoring could be omitted., Methods: We included patients with HER2-positive MBC who received > 1 cycle of trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Cardiotoxicity was defined as LVEF < 50% that declined > 10%-points and was categorized into non-severe cardiotoxicity (LVEF 40-50%) and severe cardiotoxicity (LVEF < 40%). Multivariable Cox and mixed model analyses were performed to identify risk factors associated with cardiotoxicity. Additionally, we explored the reversibility of cardiotoxicity in patients who continued trastuzumab., Results: In total, 429 patients were included. Median follow-up for cardiotoxicity was 15 months (interquartile range 8-31 months). The yearly incidence of non-severe + severe cardiotoxicity in the first and second year was 11.7% and 9.1%, respectively, which decreased thereafter. The yearly incidence of severe cardiotoxicity was low (2.8%) and stable over time. In non-smoking patients with baseline LVEF > 60% and no cardiotoxicity during prior neoadjuvant/adjuvant treatment, the cumulative incidence of severe cardiotoxicity was 3.1% after 4 years of trastuzumab. Despite continuing trastuzumab, LVEF decline was reversible in 56% of patients with non-severe cardiotoxicity and in 33% with severe cardiotoxicity., Conclusions: Serial cardiac monitoring can be safely omitted in non-smoking patients with baseline LVEF > 60% and without cardiotoxicity during prior neoadjuvant/adjuvant treatment.

Trastuzumab prolongs progression-free and overall survival in patients with human epidermal growth factor receptor 2 (HER2) positive breast cancer. However, trastuzumab treatment is hampered by cardiotoxicity, defined as a left ventricular ejection fraction (LVEF) decline with a reported incidence ranging from 3 to 27% depending on variable factors. Early identification of patients at increased risk of trastuzumab-induced myocardial damage is of great importance to prevent deterioration to irreversible cardiotoxicity. Although current cardiac monitoring with multi gated acquisition (MUGA) scanning and/or conventional 2D-echocardiography (2DE) have a high availability, their reproducibility are modest, and more sensitive and reliable techniques are needed such as 3D-echocardiography (3DE) and speckle tracking echocardiography (STE). But which other diagnostic imaging modalities are available for patients before and during trastuzumab treatment? In addition, what is the optimal frequency and duration of cardiac monitoring? At last, which biomarker monitoring strategies are currently available for the identification of cardiotoxicity in patients treated with trastuzumab?, Competing Interests: Declaration of competing interest All authors indicate no financial relationships., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Patients with HER2-positive metastatic breast cancer (MBC) treated with trastuzumab may experience durable tumor response for many years. It is unknown if patients with durable radiological complete remission (rCR) can discontinue trastuzumab. We analyzed clinical characteristics associated with rCR and overall survival (OS) in a historic cohort of patients with HER2-positive MBC and studied the effect of stopping trastuzumab in case of rCR., Methods: We included patients with HER2-positive MBC treated with first or second-line trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Data were collected from medical records. We used multivariable regression models to identify independent prognostic factors for rCR and OS. Time-to-progression after achieving rCR for patients who continued and stopped trastuzumab, and breast cancer-specific survival were also evaluated., Results: We identified 717 patients with a median age of 53 years at MBC diagnosis. The median follow-up was 109 months (IQR 72-148). The strongest factor associated with OS was achievement of rCR, adjusted hazard ratio 0.27 (95% CI 0.18-0.40). RCR was observed in 72 patients (10%). The ten-year OS estimate for patients who achieved rCR was 52 versus 7% for patients who did not achieve rCR. Thirty patients with rCR discontinued trastuzumab, of whom 20 (67%) are alive in ongoing remission after 78 months of median follow-up since rCR. Of forty patients (58%) who continued trastuzumab since rCR, 13 (33%) are in ongoing remission after 68 months of median follow-up. Median time-to-progression in the latter group was 14 months., Conclusions: Achieving rCR is the strongest predictor for improved survival in patients with HER2-positive MBC. Trastuzumab may be discontinued in selected patients with ongoing rCR. Further research is required to identify patients who have achieved rCR and in whom trastuzumab may safely be discontinued.

Purpose Purpose is to: (1) study effectiveness of the hospital-based work support intervention for cancer patients at two years of follow-up compared to usual care and (2) identify which early factors predict time to return-to-work (RTW). Methods In this multi-center randomised controlled trial (RCT), 106 (self-)employed cancer patients were randomized to an intervention group or control group and provided 2 years of follow-up data. The intervention group received patient education and work-related support at the hospital. Primary outcome was RTW (rate and time) and quality of life (SF-36), and secondary outcomes were, work ability (WAI), and work functioning (WLQ). Univariate Cox regression analyses were performed to study which early factors predict time to full RTW. Results Participants were diagnosed with breast (61%), gynaecological cancer (35%), or other type of cancer (4%). RTW rates were 84% and 90% for intervention versus control group. They were high compared to national register-based studies. No differences between groups were found on any of the outcomes. Receiving chemotherapy (HR = 2.43, 95% CI 1.59-3.73 p < 0.001), low level of education (HR = 1.65, 95% CI 1.076-2.52 p = 0.02) and low work ability (HR = 1.09 [95% CI 1.04-1.17] p = 0.02) were associated with longer time to full RTW. Conclusions We found high RTW rates compared to national register-based studies and we found no differences between groups. Future studies should therefore focus on reaching the group at risk, which consist of patients who receive chemotherapy, have a low level of education and have a low work ability at diagnosis. TRIAL REGISTRATION: Netherlands Trial Registry (NTR) (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1658): NTR1658.

Background: Early identification of cardiac dysfunction by non-invasive imaging in HER2-positive breast cancer patients treated with trastuzumab is challenging. In particular multigated acquisition (MUGA) scan, which is most widely used, is unable to detect subclinical cardiac changes. The use of N-terminal pro-brain natriuretic peptide (NT-proBNP), a serum biomarker of myocardial stress, might improve timely diagnosis., Methods: This prospective, single-center, cohort study included patients with HER2-positive breast cancer who started trastuzumab therapy. Echocardiography was scheduled at regular intervals every 3 months during one year follow-up for cardiac function monitoring. For research purposes, NT-proBNP was determined at the same time points. Trastuzumab-induced cardiotoxicity (TIC) was the primary study endpoint, defined as a left ventricular ejection fraction (LVEF) < 45%, and/or an absolute decline in LVEF > 10% since inclusion, and/or the incidence of a clinical cardiac event., Results: A total of 135 patients were enrolled between April 2008 and June 2016, with a median age of 54 years (IQR: 47-61). By three-dimensional echocardiography (3DE), the median LVEF at baseline was 62% (IQR: 58-65). At a median of 6 months (IQR: 5-11), 45 patients (33%) reached the study endpoint of TIC. Patients with TIC had a mean change of - 9.5% in LVEF (95% CI -7.2 to - 11.7; p  = 0.001) during 1 year of trastuzumab treatment. Both NT-proBNP at baseline (HR 1.04, 95% CI 1.02-1.07; p  = 0.003) and LVEF decline during anthracycline treatment prior to the start of trastuzumab (HR 1.16, 95% CI 1.07-1.25; p  < 0.001) were independently associated with development of TIC. The level of NT-proBNP during follow-up was associated too with development of TIC (HR 1.06 per 10 pmol/l difference, 95% CI 1.02-1.10; p  = 0.008). No steadily or sudden increase in NT-proBNP prior to TIC was observed., Conclusions: NT-proBNP cannot be used as a surrogate monitoring tool for trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients during the first year of treatment. Patients showing an LVEF decline during anthracycline pre-treatment appeared vulnerable for trastuzumab-induced cardiotoxicity., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s). 2019.)

Background: Aromatase inhibitors (AIs) are given as adjuvant therapy for hormone receptor-positive breast cancer in postmenopausal women, also to those with chemotherapy-induced ovarian function failure. The current analysis reports on endocrine data of patients with chemotherapy-induced ovarian function failure who were included in the phase III DATA study assessing different durations of adjuvant anastrozole after tamoxifen., Methods: We identified all patients with chemotherapy-induced ovarian function failure. Women who underwent a bilateral ovariectomy or used luteinizing hormone-releasing hormone agonists before random assignment were excluded. Plasma estradiol and follicle-stimulating hormone levels were monitored until 30 months after random assignment at local laboratories. We aimed to determine the ovarian function recovery (OFR) rate during AI use by the cumulative incidence competing risk method and analyzed the trend of estradiol levels during AI use by a nested case-control approach in which a subset of control subjects were compared with the OFR patients excluding the value at OFR diagnosis., Results: The 329 eligible patients had a median age of 50.0 years (range = 45-57 years) at random assignment. Thirty-nine patients developed OFR, corresponding with a 30-month recovery rate of 12.4%. Of these, 11 (28.2%) were age 50 years or older at AI initiation. The estradiol level decreased statistically significantly by 37.8% (95% CI = 27.4% to 46.7%) over the initial 30 months of AI treatment in both groups. However, the estradiol levels in the women who experienced OFR remained statistically significantly higher (difference = 20.6%, 95% CI = 2.0% to 42.7%) prior to OFR diagnosis compared with those who did not experience OFR., Conclusions: The risk of OFR during AI treatment in breast cancer patients with chemotherapy-induced ovarian function failure is relevant, even beyond 45 years. Furthermore, women experiencing OFR had statistically significant higher estradiol levels during AI treatment (before OFR) than those without, with potential consequences regarding efficacy.