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HTG mRNA expression for Progessive versus Stable disease in breast cancer RADICAL trial patients

ABSTRACT: Background: AZD4547 is a potent and selective inhibitor of FGFR-1, 2 and 3 receptor tyrosine kinases. Phase 1 studies both in Europe and Japan have shown that the compound is well tolerated and shows activity in patients with solid tumours. Here, we hypothesised that AZD4547 could reverse resistance to AIs such as anastrozole and letrozole. Methods: After a safety run-in study in which 6 patients had PK and safety assessments on combined AI plus AZD4547, we recruited 52 eligible patients with metastatic breast cancer who had progressed on treatment with anastrozole or letrozole. The primary objective of the phase lla study was to assess the efficacy of AZD4547 based on the change in tumour size when used in combination with either anastrozole or letrozole in ER positive breast cancer patients who have progressed on treatment with either anastrozole or letrozole in any setting. Results:. According to centrally reviewed RECIST criteria, five partial response (PR) and 8 stable disease (SD) patients were observed from a total of 50 assessable cases, giving a Clinical Benefit Rate (PR + SD) of 26% (95% CI: 14.6-40.3%). RNA-Seq was done on a subset of patients’ samples: 6 differentially-expressed-genes could distinguish those who benefited from the addition of AZD4547. Eleven patients had retinal pigment epithelial detachments (RPEDs) either in one or both eyes which was asymptomatic and reversible, although RPED recurred in one patient on re-treatment. Twenty six (50%) and 7(13%) patients had elevated phosphate and calcium, respectively. Conclusions: in a group of unselected ER positive women with aromatase inhibitor-resistant metastatic breast cancer, FGFR pathway inhibition combined with letrozole or anastrozole provided clinical benefit in a significant proportion of patients with manageable toxicity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198650 | GEO | 2022/03/18

REPOSITORIES: GEO

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Project description:Purpose Aromatase inhibitors (AIs) have an established role in breast cancer treatment. Response rates are only 50-70% in the neoadjuvant setting and lower in advanced disease. Accurate biomarkers are urgently needed to predict response in these settings and to determine which individuals will benefit from adjuvant AI therapy. Participants and Methods Pre- and on-treatment (after 2 weeks and 3 months) biopsies were obtained from 89 post-menopausal women with ER+ breast cancer receiving neoadjuvant letrozole for transcript profiling. Dynamic clinical response was assessed by three-dimensional ultrasound measurements. Results The molecular response to letrozole was characterised and a four gene classifier of clinical response was established (accuracy of 96%) based upon the level of two genes prior to treatment (one associated with immune signalling, IL6ST and the other with apoptosis, NGFRAP1) and two proliferation genes (ASPM, MCM4) at 2 weeks of therapy. The four gene signature was found to be 91% accurate in a blinded, completely independent validation dataset of patients treated with anastrozole. Matched 2 week on-treatment biopsies improved predictive power over pre-treatment biopsies alone. This signature also significantly predicted recurrence free survival (p=0.029) and breast cancer specific survival (p=0.009). We demonstrate that the test can also be performed using quantitative PCR or immunohistochemistry. Conclusion A four gene predictive model of clinical response to AIs by two weeks has been generated and validated. Deregulated immune and apoptotic responses before treatment and a failure to reduce proliferation by 2 weeks are functional characteristics of breast tumours that do not respond to AIs. 25 Pre treatment, 25 two week and 25 three month on-treatment primary breast tumour samples from the same patients. Data was analysed with two previously generated datasets, GSE55374 which was also processed on Illumina HT-12v4 BeadChips (GPL10558) and GSE20181 on Affymetrix U133A GeneChips (GPL96)

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HTG mRNA expression for Progessive versus Stable disease in breast cancer RADICAL trial patients

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