Asiatic wild ass, or kulan (
Equus hemionus kulan
) were once a key species of the Eurasian steppes and deserts. In Kazakhstan they went extinct by the 1930s. Early reintroductions have reestablished ...the species in two protected areas, but the species has reclaimed <1% of their former range and remained absent from central Kazakhstan. To initiate restoration in this vast region, we captured and transported a first group of nine wild kulan to a large pre-release enclosure in the Torgai region in 2017, and two more in 2019. We used direct observations and post-release movement data of four kulan equipped with GPS-Iridium collars to document their adaptation process in a vast novel habitat without conspecifics. For comparison with movements in the source populations, we additionally equipped two kulan in Altyn Emel National Park and six in Barsa Kelmes State Nature Reserve. The nine transported kulan formed a cohesive group with very high movement correlation in the enclosure. After release, the group initially stayed tightly together but started to break up by mid-May and all kulan travelled independently by mid-August. With 48,680–136,953 km
2
, the 95% Autocorrelated Kernel Density Estimation ranges of the reintroduced kulan were huge and about 10–100 times larger than those in the source populations. The reintroduced mares never reconnected, there was no evidence of successful reproduction, and two of the four collared mares were killed by poachers and one died of natural causes. At least one stallion survived in the wild, but the fate of the other uncollared animals remains unclear. We speculate that the fission-fusion dynamics and low movement correlation of kulan societies and the need for migratory movements harbours the risk that animals released into a novel environment loose contact with each other. This risk is likely enhanced in steppe habitats where movement constraining factors are absent. Further kulan reintroductions to the steppes and deserts of central Kazakhstan should aim to release larger groups and build up the free-ranging population quickly to reach a critical mass, increasing the chance of kulan encountering conspecifics to successfully breed and increase their chances of survival.
The introduction of aromatase inhibitors (AI) has provided more options for adjuvant treatment of postmenopausal women; they are associated with improved disease-free survival, but less commonly with ...improvements in overall survival. Current evidence suggests that women at high risk of recurrence, especially those with node-positive disease, should receive an AI for 2 years as part of their treatment, but routine prescription of AIs to postmenopausal patients with low-risk disease is not appropriate. Not only the expected benefits but also the specific toxicity of the prescribed hormone therapy, and its cost, should be considered when selecting treatment.
Treatment and outcomes of patients with HER2-positive (HER2+) metastatic breast cancer (MBC) have dramatically improved over the past 20 years. This work evaluated treatment patterns and outcomes ...according to age.
Women who initiated a treatment for HER2+ MBC between 2008 and 2016 in one of the 18 French comprehensive centers part of the ESME program were included. Objectives were the description of first-line treatment patterns, overall survival (OS), first-line progression-free survival (PFS), and prognostic factors among patients aged 70 years or more (70+), or less than 70 (<70).
Of 4045 women diagnosed with an HER2+ MBC, 814 (20%) were 70+. Standard first-line treatment (chemotherapy combined with an anti-HER2 therapy) was prescribed in 65% of 70+ versus 89% of <70 patients (p < 0.01). Median OS was 49.2 (95% CI, 47.1–52.4), 35.3 (95% CI, 31.5–37.0) and 54.2 months (95% CI, 50.8–55.7) in the whole population, in patients 70+ and <70, respectively. Corresponding median PFS1 were 12.8 (95% CI, 12.3–13.3), 11.1 (95% CI, 10.0–12.3) and 13.2 months (95% CI, 12.7–13.9), respectively. In 70+ women, initiation of non-standard first-line treatment had an independent detrimental time-varying effect on both OS and PFS (HR on OS at 1 year: chemotherapy without anti-HER2 2.79 95% CI: 2.05–3.79; endocrine therapy and/or anti-HER2 1.96 95% CI: 1.43–2.69).
In this large retrospective real-life database, older women with HER2+ MBC received standard first-line treatment less frequently than younger ones. This was independently associated with a worse outcome, but confounding factors and usual selection biases cannot be ruled out.
•Only 65% of women aged 70+ with HER2+ MBC receive a standard first-line treatment.•Median PFS1 of women 70+ with HER2+ MBC is 11.1 months (95% CI, 10.0–12.3) vs 13.2 (95% CI, 12.7–13.9) for younger ones.•Non-standard first-line treatment has a detrimental time-varying effect on both OS and PFS.
Among metastatic breast cancer (MBC) patients, those with a triple-negative breast cancer phenotype (mTNBC) have the worst prognosis, but the benefit of chemotherapy beyond second line on outcome ...remains uncertain. The purpose of this study was to identify predictive factors of outcome after third- or fourth-line chemotherapy.
The ESME-MBC database is a French prospective real-life cohort with homogeneous data collection, including patients who initiated first-line treatment for MBC (2008–2016) in 18 cancer centers. After selection of mTNBC cases, we searched for independent predictive factors (Cox proportional-hazards regression models) for overall survival (OS) on third- and fourth-line chemotherapy (OS3, OS4). We built prognostic nomograms based on the main prognostic factors identified.
Of the 22,266 MBC cases in the ESME cohort, 2903 were mTNBC, 1074 (37%) and 598 (20%) of which had received at least 3 or 4 lines of chemotherapy. PFS after first- and second-line chemotherapy (PFS1, PFS2) and number of metastatic sites ≥3 at baseline were identified by multivariate analysis as prognostic factors for both OS3 (HR = 0.76 95%CI0.66–0.88, HR = 0.55 95%CI0.46–0.65, HR = 1.36 95%CI1.14–1.62, respectively), and OS4 (HR = 0.76 95%CI0.63–0.91, HR = 0.56 95%CI0.45–0.7, HR = 1.37 95%CI1.07–1.74), respectively. In addition, metastasis-free interval was identified as a prognostic factor for OS3 (p = 0.01), while PFS3 influenced OS4 (HR = 0.75 95%CI0.57–0.98). Nomograms predicting OS3 and OS4 achieved a C-index of 0.62 and 0.61, respectively.
The duration of each previous PFS is a major prognostic factor for OS in mTNBC patients receiving third- or fourth-line chemotherapy. The clinical utility of nomograms including this information was not demonstrated.
•After 3rd- or 4th-line therapy, PFS remained linear in the majority of women with metastatic triple-negative breast cancer.•The duration of each previous PFS had an impact on the OS associated with subsequent lines.•PFS2 was more strongly predictive of outcome than PFS1 for third-line therapy.•PFS2 and PFS3 had an impact on outcome irrespective of PFS1 for fourth-line therapy.•The clinical utility of nomograms including duration of each previous PFS to predict OS was not sufficient.
For young patients with hormone receptor-positive early breast cancer, tamoxifen for at least 5 years is the standard endocrine treatment. Prolonged endocrine treatment over 5 years is recommended ...for patients with high risk of late relapse. When adjuvant chemotherapy is indicated, prolonged iatrogenic amenorrhea is a strong pronostic factor. WIthout persistant amenorrhea after chemotherapy, it is indicated to associate ovarian suppression to the endocrine treatment. Optimal duration of this induced amenorrhea is unknown.
For most patients suffering from recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC), chemotherapy is the main option after considering surgery and reirradiation. Cetuximab ...combined with a platinum-fluorouracil regimen (EXTREME) has been the standard of care for over a decade. Nevertheless, a significant number of patients remain unfit for this regimen because of age, severe comorbidities, or poor performance status. The aim of this study is to investigate an alternative regimen with sufficient efficacy and safety.
We reviewed retrospectively the medical charts of all patients treated with paclitaxel, carboplatin, and cetuximab (PCC) at our institution. Eligibility criteria were as follows: first-line R/M-HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx not suitable for local therapy, cisplatin, and/or 5-FU ineligibility, ECOG-PS: 0-2. PCC consisted of paclitaxel 80 mg/m
, carboplatin AUC 2, and cetuximab at an initial dose of 400 mg/m
then 250 mg/m
, for 16 weekly administrations followed by cetuximab maintenance for patients for whom a disease control was obtained. The primary endpoint was overall survival (OS), and secondary endpoints were overall response rate (ORR), progression free survival (PFS), and safety.
We identified 60 consecutive patients treated with PCC between 2010 and 2016 at our institution. Thirty-one patients (52%) were ECOG-PS 2. Fifty-five patients (92%) were cisplatin ineligible. ORR was 43.3% (95% CI, 30.8-55.8), and disease control rate was 65% (95% CI, 52.9-77.1). With a median follow-up of 35.7 months (IQR 28.6-48.8), median PFS was 5.8 months (95% CI, 4.5-7.2), and median OS was 11.7 months (95% CI, 7.5-14.8). For ECOG-PS 0-1 patients, median OS was 14.8 months (95% CI, 12.2-21.7) while it was only 7.5 months (95%CI: 5.5-12.7) for ECOG-PS 2 patients (
< 0.04). Grades III-IV toxicities occurred in 30 patients (50%). Most toxicities were hematologic. Six patients (10%) had febrile neutropenia. Nonhematologic toxicities were reported such as cutaneous toxicities, neuropathy, infusion-related reactions, or electrolyte disorders.
The weekly PCC regimen seems to be an interesting option in cisplatin-unfit patients. This study shows favorable PFS and OS when compared with what is achieved with the EXTREME regimen and a high controlled disease rate with predictable and manageable toxicities even in the more fragile population.
Background
Early access program (formerly cohort Temporary Authorization for Use) was granted for trastuzumab deruxtecan (T‐DXd) in France based on DESTINY‐Breast01 trial which demonstrated its ...efficacy and safety in HER2‐positive metastatic/unresectable breast cancer after ≥2 anti‐HER2‐based regimens received at metastatic stage.
Methods
This multicenter real‐world early access program included HER2‐positive metastatic/unresectable breast patients pretreated with at least two lines of anti‐HER2 regimens who received T‐DXd 5.4 mg/kg intravenously in monotherapy every 3 weeks.
Results
Four hundred and fifty‐nine patients (median age, 58 years; hormone receptor‐positive, 67%; brain metastases, 28.1%) received T‐DXd. Before inclusion, 81.7% of patients had radiation therapy and 76.5% had undergone surgery. Median number of prior metastatic treatment lines was four (range, 2–22); 99.8% patients had received trastuzumab, 94.8% trastuzumab emtansine and 79.3% pertuzumab. Follow‐up was performed from September 30, 2020 to March 30, 2021; when the early access program stopped, the median duration of T‐DXd treatment was 3.4 (range, 0–7.8) months. In 160 patients with available tumor assessment, objective response rate was 56.7% and 12.1% had progression. In 57 patients with available brain tumor assessment, complete or partial intracranial response was reported for 35.7% patients and 5.4% had progression. A total of 17 (3.7%) patients with interstitial lung disease (ILD) was reported with no cases of ILD‐related death.
Conclusions
In this early access program in patients with heavily pretreated HER2‐positive metastatic/unresectable breast cancer, T‐DXd had antitumor activity with a similar response to that reported in previous clinical studies. T‐DXd was well tolerated and no new safety signals were observed.
The European patent for intravenous trastuzumab lapsed in 2017, and this stimulated research into a number of trastuzumab biosimilars. Quality assessment of their development and clinical results ...might enable establishment of a clinical hierarchy of these agents. This editorial will underline the key points for consideration when determining such an evaluation.
Rarely, deleterious mutations could also cause HER2 overexpression without any amplification-supporting processes. ...the various mechanisms that lead to a HER2-positive status, combined with the ...heterogeneity of associated genetic breast cancer subtypes, suggests the need for tailored therapeutic strategies. Randomised trials have shown that trastuzumab emtansine improves clinical outcomes for patients with HER2-positive metastatic breast cancer and has a more acceptable safety profile than standard treatment regimens.5 Although standard trastuzumab-containing regimens in a neoadjuvant setting did not lead to pathological complete responses in patients with early-stage breast cancer, a switch to trastuzumab emtansine instead of pursuing adjuvant trastuzumab showed a survival benefit.6 How trastuzumab emtansine could become the backbone of anti-HER2 treatment strategies is still a matter of debate. Both molecules can inhibit the PI3K signalling pathway and HER2 extracellular domain shedding and can elicit an antibody-dependent cellular cytotoxicity response on binding of the Fab region to HER2 on cancer cells and binding of the Fc region to FcγRs on immune-effector cells.
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