Purpose
The concomitant use of intravenous (IV) iron as a supplement to erythropoiesis-stimulating agents in patients with chemotherapy-induced anemia is controversial. This study was designed to ...evaluate the efficacy and safety of darbepoetin alfa given with IV iron versus with local standard practice (oral iron or no iron).
Patients and Methods
In this multicenter, randomized, open-label, phase III study, 396 patients with nonmyeloid malignancies and hemoglobin (Hb) less than 11 g/dL received darbepoetin alfa 500 μg with (n = 200) or without (n = 196) IV iron once every 3 weeks (Q3W) for 16 weeks.
Results
The hematopoietic response rate (proportion of patients achieving Hb ≥ 12 g/dL or Hb increase of ≥ 2 g/dL from baseline) was significantly higher in the IV iron group: 86% versus 73% in the standard practice group (difference of 13% 95% CI, 3% to 23%; P = .011). Fewer RBC transfusions (week 5 to the end of the treatment period) occurred in the IV iron group: 9% versus 20% in the standard practice group (difference of −11% 95% CI, −18% to −3%; P = .005). Both treatments were well tolerated with no notable differences in adverse events. Serious adverse events related to iron occurred in 3% of patients in the IV iron group and were mostly gastrointestinal in nature.
Conclusion
Addition of IV iron to darbepoetin alfa Q3W in patients with chemotherapy-induced anemia was well tolerated, resulting in an improved hematopoietic response rate and lower incidence of transfusions compared with darbepoetin alfa alone.
Oestrogen receptor positive (ER+)/HER-2 negative breast cancer (BC) is considered to be an immunologically cold tumour compared to triple negative breast cancer. Therefore, the tumour ...microenvironment (TME) of ER+/HER-2 negative BC is understudied. The aim of this project is to investigate the TME and the immune response during neoadjuvant endocrine therapy (NET) and to correlate this with the treatment response in a real life setting.
Expression of immune checkpoint receptors and immune cells was examined immunohistochemically, pre- and post-NET in a cohort of 56 ER+/HER-2 negative BC patients. They were treated with tamoxifen (n = 16), an aromatase inhibitor (n = 40) or a combination of an aromatase inhibitor with a PI3K inhibitor (n = 11) for a median duration of 6 months (range 1-32 months). Immunohistochemical staining with monoclonal antibodies for PDL-1, PD-1, TIM-3, LAG-3, CTLA-4, CD4, CD68 and FOXP3 were performed. All staining procedures were done according to validated protocols, and scoring was done by a pathologist specialized in breast cancer. Positivity was defined as staining >1% on TILs. Response to NET was evaluated according to tumour size change on imaging and Ki-67 change.
The median age was 61.02 (37-90) years. Diameter of tumour size decreased with a mean of 8.1 mm (-16 mm to 45 mm) (p < 0.001) during NET and the value of Ki-67 value decreased with a median of 9 after NET (p < 0.001). An increase in PD-L1 expression after NET showed a trend towards significant (p = 0.088) and CD-4+ T cells significantly increased after NET (p = 0.03). A good response to NET defined as a decrease in tumour size and/or decrease of Ki-67 was found to be associated with a longer duration of NET, a change of CD4+ T-cells and a higher number of CD68+ tumour-associated macrophages before the start of NET.
The immune microenvironment plays an important role in ER+/HER-2 negative BC. NET influences the composition and functional state of the infiltrating immune cells. Furthermore, changes in the immune microenvironment are also associated with treatment response.
•Increased TILs are an adverse prognostic factor for overall survival in HER-2 negative luminal breast cancer.•Increased FOXP3 + TIL infiltration in ER positive breast cancer can be considered as a ...poor prognostic factor.•Tumour-associated macrophages −2 plays a roll in the chemotherapy resistance for HR positive breast tumours.•Tamoxifen reduce anti-tumour responses of CD4+ t cells in breast cancer.•Neoadjuvant treatment with an aromatase inhibitors caused modification of TILs composition.•TGF-β plays an important roll in HR positive breast cancer.
: Although hormone receptor positive/HER2-negative (HR +/HER2-) breast cancer is the most diagnosed breast cancer type, the immunologic aspects HR positive breast cancer (BC) has been neglected until recently. The purpose of this paper is to review the current knowledge of the immune environment in HR positive BC and the potential use of immunotherapy in these patients.
: A computer-based literature research was carried out using PubMed, American Society of Clinical Oncology Annual Meeting (ASCO) and San Antonio Breast Cancer Symposium (SABCS).
: The tumour microenvironment (TME), with infiltrating immune cells, plays an important role in HR positive BC. However, the effects of these immune cells are different in the luminal cancers compared to the other breast cancer types. Even though PD-1 and PD-L1 are less expressed in HR positive BC, pathological complete response (pCR) was more often seen after PD-1 inhibitor treatment in patients with an increased expression. The studies support the assertion that endocrine therapy has immunomodulatory effect.
: The reviewed literature indicates that immune cells play an important role in HR positive BC. Considerably more research is needed to determine the real effect of the TME in this patient group.
Optimal management of breast ductal carcinoma in situ (DCIS) is controversial, and many patients are still overtreated. The local death of myoepithelial cells (MECs) is believed to be a pre-requisite ...to tumor invasion. We thus hypothesized that loss of CD10 expression, a MEC surface peptidase, would signify basement membrane disruption and confer increased risk of relapse in DCIS. The aim of our study was to retrospectively evaluate the prognostic value of CD10 in DCIS.
CD10 expression was evaluated by quantitative RT-PCR and immunohistochemistry using paraffin-embedded samples of normal breast tissue (n = 11); of morphologically normal ducts associated with DCIS (n = 10); and of DCIS without an invasive component (n = 154).
CD10 immunostaining was only observed in MECs in normal tissue and in DCIS. Normal tissue showed high mRNA expression levels of CD10, whereas DCIS showed a variable range. After a median follow-up of 6 years, DCIS with CD10 expression below the levels observed in normal tissue (71%) demonstrated a higher risk of local relapse (HR = 1.88; 95CI:1.30-2.70, p = 0.001) in univariate analysis. No relapse was observed in patients expressing high CD10 mRNA levels (29%) similar to the ones observed in normal tissue. In multivariate analysis including known prognostic factors, low CD10 mRNA expression remained significant (HR = 2.25; 95%CI:1.24-4.09, p = 0.008), as did the recently revised Van Nuys Prognostic Index (VNPI) score (HR = 2.03; 95%CI:1.23-3.35, p = 0.006).
The decrease of CD10 expression in MECs is associated with a higher risk of relapse in DCIS; this knowledge has the potential to improve DCIS management.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival ...interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine.
This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0–1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5·4 mg/kg or trastuzumab emtansine 3·6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03529110.
Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab deruxtecan (n=261) or trastuzumab emtansine (n=263). Median duration of study follow-up was 28·4 months (IQR 22·1–32·9) with trastuzumab deruxtecan and 26·5 months (14·5–31·3) with trastuzumab emtansine. Median progression-free survival by blinded independent central review was 28·8 months (95% CI 22·4–37·9) with trastuzumab deruxtecan and 6·8 months (5·6–8·2) with trastuzumab emtansine (hazard ratio HR 0·33 95% CI 0·26–0·43; nominal p<0·0001). Median overall survival was not reached (95% CI 40·5 months–not estimable), with 72 (28%) overall survival events, in the trastuzumab deruxtecan group and was not reached (34·0 months–not estimable), with 97 (37%) overall survival events, in the trastuzumab emtansine group (HR 0·64 95% CI 0·47–0·87; p=0·0037). The number of grade 3 or worse treatment-emergent adverse events was similar in patients who received trastuzumab deruxtecan versus trastuzumab emtansine (145 56% patients versus 135 52% patients). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 39 (15%) patients treated with trastuzumab deruxtecan and eight (3%) patients treated with trastuzumab emtansine, with no grade 4 or 5 events in either group.
Trastuzumab deruxtecan showed a significant improvement in overall survival versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming trastuzumab deruxtecan as the standard of care in the second-line setting. A manageable safety profile of trastuzumab deruxtecan was confirmed with longer treatment duration.
Daiichi Sankyo and AstraZeneca.
: Ductal carcinoma in situ (DCIS) is considered a heterogeneous premalignant condition of the breast with a certain probability for progressing to malignancy. There is no standard of care. The ...updated Van Nuys Prognostic Index (VNPI) 2003 is a clinical tool in treatment decision making. This study assessed the prognostic value of the VNPI after integration of proliferative biomarkers (GGI and Ki‐67). DCIS samples were divided into three VNPI subgroups (low risk score 4–6, intermediate risk score 7–9, high risk score 10–12) based on nuclear grade ± necrosis, tumor size, margin width, and age. Nuclear grade was substituted by the genomic grade index (GGI) to generate the VNPI‐GGI and combined with the Ki‐67 to generate the VNPI‐Ki67. Disease‐free survival was calculated by Kaplan–Meier survival plots with log‐rank significance. Multiple regression analysis was carried out using Cox proportional hazard regression analysis. A total of 88 cases (median age 54 years) with representative tissue were identified out of 168 DCIS patients. Median follow‐up was more than 5 years. Ten patients developed an ipsilateral recurrence of whom nine were invasive: six patients were classified in the VNPI subgroup 2 and three patients in the VNPI subgroup 3. One non‐invasive recurrence (DCIS) was classified in the VNPI subgroup III. A statistical association was observed between a high VNPI score and a higher risk of recurrence (HR = 7.72 95% CI 1.01–58.91, p = 0.049). Ki‐67 did not improve the prognostic value of VNPI (HR = 6.5, 95% CI 0.80–53.33, p = 0.08). In contrast, the VNPI‐GGI could identify more accurately high‐risk DCIS patients with early relapses within 5 years (HR = 18.14 95% CI 1.75–188, p = 0.015). GGI incorporated into the VNPI improved its prognostic value for DCIS, especially for identifying early relapses. This method should be validated and incorporated in future prospective clinical DCIS trials.
Despite the high incidence of metastatic breast cancer and its related mortality in the elderly population, our knowledge about optimal treatment for older patients with cancer is far from adequate. ...We aimed to evaluate the efficacy of dual anti-HER2 treatment with or without metronomic chemotherapy in older patients with HER2-positive metastatic breast cancer.
We did a multicentre, open-label, randomised, phase 2 trial in 30 centres from eight countries in Europe, in patients with histologically proven, HER2-positive metastatic breast cancer, without previous chemotherapy for metastatic disease, who were 70 years or older, or 60 years or older with confirmed functional restrictions defined by protocol, and had a life expectancy of more than 12 weeks and a performance status according to WHO scale of 0–3. Eligible patients were randomly assigned (1:1) by an online randomisation system based on the minimisation method to receive metronomic oral cyclophosphamide 50 mg per day plus trastuzumab and pertuzumab, or trastuzumab and pertuzumab alone. Trastuzumab was given intravenously with a loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks. Pertuzumab was given intravenously with a loading dose of 840 mg, followed by 420 mg every 3 weeks. Patients were stratified by hormone receptor positivity, previous HER2 treatment, and baseline geriatric screening. The primary endpoint was investigator-assessed progression-free survival at 6 months as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A difference of 10% or greater between the two groups was sought. Efficacy analyses were by intention to treat; safety was assessed in all patients who received at least one dose of study treatment. In case of progression, all patients were offered trastuzumab emtansine. This trial is registered with ClinicalTrials.gov, number NCT01597414, and is completed.
Between July 2, 2013, and May 10, 2016, 80 patients, of whom 56 (70%) had a potential frailty profile according to the geriatric screening G8 score (≤14), were randomly assigned to receive trastuzumab and pertuzumab (n=39) or trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (n=41). Estimated progression-free survival at 6 months was 46·2% (95% CI 30·2–60·7) with trastuzumab and pertuzumab versus 73·4% (56·6–84·6) with trastuzumab and pertuzumab plus metronomic oral cyclophosphamide (hazard ratio HR 0·65 95% CI 0·37–1·12, p=0·12). At a median follow-up of 20·7 months (IQR 12·5–30·4), the median progression-free survival was 5·6 months (95% CI 3·6–16·8) with trastuzumab and pertuzumab versus 12·7 months (6·7–24·8) with the addition of metronomic oral cyclophosphamide. The most frequent grade 3–4 adverse events were hypertension (in six 15% of 39 patients in the trastuzumab and pertuzumab group vs five 12% of 41 in the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group), diarrhoea (four 10% vs five 12%), dyspnoea (two 5% vs four 10%), fatigue (three 8% vs two 5%), pain (two 5% vs two 5%), and a thromboembolic event (0 0% vs four 10%). Severe cardiac toxicities were occasionally observed in both groups. In the trastuzumab and pertuzumab group four patients died without progression, due to cardiac arrest during treatment (n=1), peritoneal infection (n=1), respiratory failure (n=1), and sudden death without a specified cause (n=1). In the trastuzumab and pertuzumab plus metronomic oral cyclophosphamide group, one patient died from heart failure.
Addition of metronomic oral cyclophosphamide to trastuzumab plus pertuzumab in older and frail patients with HER2-positive metastatic breast cancer increased median progression-free survival by 7 months compared with dual HER2 blockade alone, with an acceptable safety profile. Trastuzumab and pertuzumab plus metronomic oral cyclophosphamide, followed by trastuzumab emtansine after disease progression, might delay or supersede the need for taxane chemotherapy in this population.
F Hoffmann-La Roche.
•Cancer patients with COVID-19 have a higher morbidity and mortality.•Particularly patients with ongoing or recent cancer treatment, metastatic solid tumors and hematological malignancies are at ...risk.•Underlying immunosuppression, elevated cytokine levels, altered expression of the angiotensin converting enzyme (ACE-2) and TMPRSS2, and a prothrombotic status in cancer patients may fuel the effects of a SARS-CoV-2 sepsis.•The gene expression level of ACE2 may be an indicator of the susceptibility to SARS-CoV-2 infection, while TMPRSS2 plays a supporting role.•Better knowledge of the mechanisms involved may be a tool to identify high risk patients and to prevent severe complications by targeting the involved pathways.
The outbreak of the SARS-CoV-2 pandemic has overwhelmed health care systems in many countries. The clinical presentation of the SARS-CoV-2 varies between a subclinical or flu-like syndrome to that of severe pneumonia with multi-organ failure and death. Initial reports have suggested that cancer patients may have a higher susceptibility to get infected by the SARS-CoV-2 virus but current evidence remains poor as it is biased by important confounders. Patients with ongoing or recent cancer treatment for advanced active disease, metastatic solid tumors and hematological malignancies are at higher risk of developing severe COVID-19 respiratory disease that requires hospitalization and have a poorer disease outcome compared to individuals without cancer. However it is not clear whether these are independent risk factors, or mainly driven by male gender, age, obesity, performance status, uncontrolled diabetes, cardiovascular disease and various other medical conditions. These often have a greater influence on the probability to die due to SARS-CoV-2 then cancer. Delayed diagnosis and suboptimal cancer management due to the pandemic results in disease upstaging and has considerable impact cancer on specific death rates. Surgery during the peak of the pandemic seems to increase mortality, but there is no convincing evidence that adjuvant systemic cancer therapy and radiotherapy are contraindicated, implicating that cancer treatment can be provided safely after individual risk/benefit assessment and some adaptive measures. Underlying immunosuppression, elevated cytokine levels, altered expression of the angiotensin converting enzyme (ACE-2) and TMPRSS2, and a prothrombotic status may fuel the effects of a SARS-CoV-2 in some cancer patients, but have the potential to be used as biomarkers for severe disease and therapeutic targets. The rapidly expanding literature on COVID-19 should be interpreted with care as it is often hampered by methodological and statistical flaws.
Background: Docetaxel, ifosfamide and cisplatin have all shown activity in squamous cell carcinoma of the head and neck (SCCHN).
The optimal combination of the three drugs is, however, unknown. ...Considering the favorable results of taxane-containing triplets
as induction chemotherapy in locally advanced (LA) SCCHN, DIP (docetaxel, ifosfamide, cisplatin) was studied in this setting
as part of a phase I dose- and sequence-exploring study. Patients and Methods: D (60 or 75 mg/m 2 ) was given by 60-min infusion on day 1, I (1000 mg/m 2 /day), with mesna until 12 hours after I, by 24-h infusion days 1-5, and P (50 or 75 mg/m 2 ) by 24-h infusion on days 1 or 5. The cycles were repeated every 21 days. Toxicities according to the National Cancer Institute
Common Toxicity Criteria version 2 (NCI-CTC2) were evaluated weekly and response was evaluated every 2 cycles according to
the World Health Organization (WHO) criteria. Thereafter, radiotherapy (RT, cumulative dose 70 Gy) or chemoradiation (CRT),
both with conventional fractionation, were planned. Results: Twenty-two patients (18 male, 4 female; age 41-66 years, performance
status 0-1, 2 T4N0, 3 T3N2, 11 T4N2, 3 T unknown N3, 1 T1N3 and 2 T4N3) received a median of 4 DIP cycles (range 1-5). Grade
4 neutropenia occurred in 18 patients, grade 3 and 4 thrombocytopenia in 5 and 1 patients, respectively, and grade 3 anemia
in 5 patients. Gastrointestinal and mucosal toxicities were generally mild/moderate. Vascular complications (probably not
DIP-related) precluded local treatment in two patients. Moreover, one patient died on day 13 of the first DIP (neutropenic
sepsis and myocardial infarction). The remaining patients received RT (n=2) or CRT (n=17; 16 of these with gemcitabine). The
response to 2 Ã DIP was 95% (1 complete response, 19 partial responses, 1 stable disease); the complete response rate increased
to 42% after 4 Ã DIP. No dose or sequence effect was evident. The minimum follow-up of the surviving patients was 51 months,
with median relapse-free survival of 13.8 months and median overall survival of 18.8 months. Only four patients relapsed at
distant sites. Conclusion: DIP is highly active in previously untreated LA SCCHN, however, toxicity of DIP in this population
is substantial.
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