The NEOLETEXE Trial: A Neoadjuvant Cross-Over Study Exploring the Lack of Cross Resistance Between Aromatase Inhibitors

Bahrami, Nazli; Sauer, Torill; Engebretsen, Siri; Aljabri, Belal; Bemanian, Vahid; Lindstrøm, Jonas Christoffer; Lüders, Torben; Kristensen, Vessela N.; Lorentzen, Annika; Loeng, Marie; Ødegård, Hilde Presterud; Kvaløy, Jan Øyvind; Vestøl, Ingeborg Berge; Geisler, Stephanie; Gravdehaug, Berit; Gundersen, J; Geisler, Jürgen

doi:10.2217/fon-2019-0258

Cited by 8 publications

(12 citation statements)

References 35 publications

(37 reference statements)

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“…From February 2015 to November 2019, patients with biopsy-proven locally advanced oestrogen receptor (ER)positive breast cancer and human epidermal growth factor receptor 2 (HER-2)-negative status suitable for NET were eligible for this prospective, open-label, randomized sub-study of the Neoletexe trial, (Fig. 1) [36]. All participants had to be postmenopausal to benefit from aromatase inhibition.…”

Section: Materials and Methods Study Populationmentioning

confidence: 99%

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Accuracy of breast MRI in patients receiving neoadjuvant endocrine therapy: comprehensive imaging analysis and correlation with clinical and pathological assessments

Reis

Lindstrøm

Boavida

et al. 2020

Breast Cancer Res Treat

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Purpose To assess the accuracy of magnetic resonance imaging (MRI) measurements in locally advanced oestrogen receptor-positive and human epidermal growth factor receptor 2-negative breast tumours before, during and after neoadjuvant endocrine treatment (NET) for evaluation of tumour response in comparison with clinical and pathological assessments. Methods This prospective study enrolled postmenopausal patients treated neoadjuvant with letrozole and exemestane given sequentially in an intra-patient cross-over regimen. Fifty-four patients were initially recruited, but only 35 fulfilled the inclusion criteria and confirmed to participate with a median age of 77. Tumours were scanned with MRI prior to treatment, during the eighth week of treatment and prior to surgery. Additionally, changes in longest diameter on clinical examination (CE) and tumour size at pathology were determined. Pre- and post-operative measurements of tumour size were compared in order to evaluate tumour response. Results The correlation between post-treatment MRI size and pathology was moderate and higher with a correlation coefficient (r) 0.64 compared to the correlation between CE and pathology r = 0.25. Post-treatment MRI and clinical results had a negligible bias towards underestimation of lesion size. Tumour size on MRI and CE had 0.82 cm and 0.52 cm lower mean size than tumour size measured by pathology, respectively. Conclusions The higher correlation between measurements of residual disease obtained on MRI and those obtained with pathology validates the accuracy of imaging assessment during NET. MRI was found to be more accurate for estimating complete responses than clinical assessments and warrants further investigation in larger cohorts to validate this finding.

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Section: Materials and Methods Study Populationmentioning

confidence: 99%

“…5 (Fig. 1) [36]. Calliper measurements of maximum tumour size (in centimetres) and tumour quadrant location were recorded.…”

Section: Clinical Assessmentmentioning

confidence: 99%

Accuracy of breast MRI in patients receiving neoadjuvant endocrine therapy: comprehensive imaging analysis and correlation with clinical and pathological assessments

Reis

Lindstrøm

Boavida

et al. 2020

Breast Cancer Res Treat

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“…Our prospective, randomized, open-label, cross-over substudy from the NEOLETEXE trial enrolled 71 participants with histologically confirmed unilateral strongly ER + , human epidermal growth factor receptor 2 (HER2)-negative LABC between February 2015 and December 2020 at Akershus University Hospital (Fig. 3 ) [ 24 ]. The 50 eligible participants had to be postmenopausal to benefit from neoadjuvant aromatase inhibitors (NAAI) with no or limited distant metastasis.…”

Section: Methodsmentioning

confidence: 99%

Correlation between MRI morphological response patterns and histopathological tumor regression after neoadjuvant endocrine therapy in locally advanced breast cancer: a randomized phase II trial

Reis

Thomas

Lahooti

et al. 2021

Breast Cancer Res Treat

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Purpose To correlate MRI morphological response patterns with histopathological tumor regression grading system based on tumor cellularity in locally advanced breast cancer (LABC)-treated neoadjuvant with third-generation aromatase inhibitors. Methods Fifty postmenopausal patients with ER-positive/HER-2-negative LABC treated with neoadjuvant letrozole and exemestane given sequentially in an intra-patient cross-over regimen for at least 4 months with MRI response monitoring at baseline as well as after at least 2 and 4 months on treatment. The MRI morphological response pattern was classified into 6 categories: 0/complete imaging response; I/concentric shrinkage; II/fragmentation; III/diffuse; IV/stable; and V/progressive. Histopathological tumor regression was assessed based on the recommendations from The Royal College of Pathologists regarding tumor cellularity. Results Following 2 and 4 months with therapy, the most common MRI pattern was pattern II (24/50 and 21/50, respectively). After 4 months on therapy, the most common histopathological tumor regression grade was grade 3 (21/50). After 4 months an increasing correlation is observed between MRI patterns and histopathology. The overall correlation, between the largest tumor diameter obtained from MRI and histopathology, was moderate and positive (r = 0.50, P-value = 2e-04). Among them, the correlation was highest in type IV (r = 0.53). Conclusion The type II MRI pattern “fragmentation” was more frequent in the histopathological responder group; and types I and IV in the non-responder group. Type II pattern showed the best endocrine responsiveness and a relatively moderate correlation between sizes obtained from MRI and histology, whereas type IV pattern indicated endocrine resistance but the strongest correlation between MRI and histology.

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“…1) is a neoadjuvant, randomized, open-label, intra-patient, cross-over trial with the intention to study the effects of sequential aromatase inhibition by type-I aromatase inhibitor letrozole and type-II aromatase inactivator exemestane in a randomized, intra-patient cross-over fashion in vivo. The trial has been approved by the Regional Ethics Committee of South-East Norway (project number 2015/84) [20]. In this particular sub-study, a total of 39 postmenopausal women, all diagnosed with locally advanced, ER-positive and HER-2 negative primary cancer were included (Table 1).…”

Section: Trial Design and Patientsmentioning

confidence: 99%

“…However, the precise explanation for the observed lack of cross-resistance between steroidal and nonsteroidal aromatase inhibitors is still unknown and it has been suggested that a detailed understanding of this clinical phenomenon may potentially provide a new strategy to treat hormone-sensitive breast cancer [18,19]. To investigate the fundamental differences in the effects caused by non-steroidal AIs and steroidal AIs in vivo, we designed the NEOLETEXE-trial [20]; (Figure 1). The present manuscript reports the results of a planned cytokine-substudy of the NEOLETEXE-trial.…”

Section: Introductionmentioning

confidence: 99%

Lack of Cross-resistance Between Non-steroidal and Steroidal Aromatase Inhibitors in Breast Cancer Patients: The Potential Role of the Adipokine Leptin.

Bahrami

Jabeen

Sauer

et al. 2020

Preprint

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Background: The aromatase inactivator exemestane may cause clinical disease stabilization following progression on non-steroidal aromatase inhibitors like letrozole in patients with metastatic breast cancer, indicating that additional therapeutic effects, not necessarily related to estrogen-suppression, may be involved in this well-known “lack of cross-resistance”. Experimental design: Postmenopausal women with ER positive, HER-2 negative, locally advanced breast cancer were enrolled in the NEOLETEXE-trial and randomized to sequential treatment starting with either letrozole (2.5 mg o.d.) or exemestane (25 mg o.d.) followed by the alternative aromatase inhibitor. Serum levels of 54 cytokines, including 12 adipokines were assessed using the Luminex xMAP technology (multiple ELISA). Results: Serum levels of leptin were significantly decreased during treatment with exemestane (p < 0.001), regardless whether exemestane was given as first or second neoadjuvant therapy. In contrast, letrozole caused a non-significant increase in serum leptin levels in vivo. Conclusions: Our findings suggest an additional and direct effect of exemestane on CYP-19 (aromatase) synthesis presumably due to effects on the CYP19 promoter use that is not present during therapy with non-steroidal aromatase inhibitors. Our findings provide a reasonable explanation for the clinically observed lack of cross-resistance between nonsteroidal and steroidal aromatase inhibitors in breast cancer patients.Trial registration: registered on March 23rd. 2015 in the National trial database of Norway (Registration number: REK-SØ-84-2015).

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The NEOLETEXE Trial: A Neoadjuvant Cross-Over Study Exploring the Lack of Cross Resistance Between Aromatase Inhibitors

Cited by 8 publications

References 35 publications

Accuracy of breast MRI in patients receiving neoadjuvant endocrine therapy: comprehensive imaging analysis and correlation with clinical and pathological assessments

Accuracy of breast MRI in patients receiving neoadjuvant endocrine therapy: comprehensive imaging analysis and correlation with clinical and pathological assessments

Correlation between MRI morphological response patterns and histopathological tumor regression after neoadjuvant endocrine therapy in locally advanced breast cancer: a randomized phase II trial

Lack of Cross-resistance Between Non-steroidal and Steroidal Aromatase Inhibitors in Breast Cancer Patients: The Potential Role of the Adipokine Leptin.

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