Convergent evolution of resistance pathways during early stage breast cancer treatment with combination cell cycle (CDK) and endocrine signalling inhibitors
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE158724 | GEO | 2021/02/09
REPOSITORIES: GEO
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Project description:Invasive lobular cancer (ILC) accounts for approximately 10-15% of breast carcinomas and although it responds poorly to neoadjuvant chemotherapy, it appears to respond well to endocrine therapy. Pre- and on-treatment (after 2 weeks and 3 months) biopsies and surgical samples were obtained from 14 post-menopausal women with ER+ histologically confirmed ILC who responded to 3 months of neoadjuvant letrozole and were compared with a cohort of 14 responding infiltrating ductal carcinomas (IDCs) matched on clinicopathological features by gene expression profiling. Dynamic clinical response was assessed using periodic 3D ultrasound measurements performed during treatment and defined as a reduction of >70% in tumour volume by 3 months. The changes in gene expression in response to letrozole were highly consistent between responding ILC and IDC tumours, genes involved in proliferation were down-regulated and those involved with immune function and ECM remodelling were up-regulated. However, molecular differences between the histological subtypes were maintained upon treatment. This is the first study of molecular changes in ILC in response to endocrine therapy to date. The genes which change on letrozole are highly consistent between ILC and IDC. Differences in gene expression between ILC and IDC at diagnosis and are maintained at each time point on treatment. 14 Pre treatment, 10 two week and 14 three month on-treatment ILC and 14 Pre treatment, 14 two week and 14 three month on-treatment IDC samples from the same patients. Pre- and on-treatment samples from 7ILC & 6IDC patients were profiled on Illumina HT-12v4 (GPL10558) and samples from 7ILC and 8 IDC patients were profiled previously on Affymetrix U133A (GPL96) see GSE20181
2014-08-11 | E-GEOD-55374 | biostudies-arrayexpress
Project description:Sequential patient-matched samples treated with extended neoadjuvant therapy were studied. Long-term treatment (letrozole) induced changes in dormant and resistant patients were determined. Samples were classified as pre-treatment (timepoint1, <0 days), early-on treatment (timepoint2, 0-120 days) and long-term treatment (timepoint4, >120 days).
2019-01-05 | GSE111563 | GEO
Project description:Invasive lobular cancer (ILC) accounts for approximately 10-15% of breast carcinomas and although it responds poorly to neoadjuvant chemotherapy, it appears to respond well to endocrine therapy. Pre- and on-treatment (after 2 weeks and 3 months) biopsies and surgical samples were obtained from 14 post-menopausal women with ER+ histologically confirmed ILC who responded to 3 months of neoadjuvant letrozole and were compared with a cohort of 14 responding infiltrating ductal carcinomas (IDCs) matched on clinicopathological features by gene expression profiling. Dynamic clinical response was assessed using periodic 3D ultrasound measurements performed during treatment and defined as a reduction of >70% in tumour volume by 3 months. The changes in gene expression in response to letrozole were highly consistent between responding ILC and IDC tumours, genes involved in proliferation were down-regulated and those involved with immune function and ECM remodelling were up-regulated. However, molecular differences between the histological subtypes were maintained upon treatment. This is the first study of molecular changes in ILC in response to endocrine therapy to date. The genes which change on letrozole are highly consistent between ILC and IDC. Differences in gene expression between ILC and IDC at diagnosis and are maintained at each time point on treatment.
2014-08-11 | GSE55374 | GEO
Project description:Sequential patient-matched samples treated with extended neoadjuvant therapy were studied. Samples were classified as pre-treatment (timepoint1, <0 days), early-on treatment (timepoint2, 0-120 days) and long-term treatment (timepoint4, >120 days).
2019-02-27 | PXD009328 | Pride
Project description:In this study, we found that combination treatment of breast cells with CK1 inihbitor (D 4476) and CDK4/6 inhibitor (Ribociclib) exhibited greatly enhanced therapeutic efficacy than CDK4/6 inhiitor single treatment
2021-08-10 | GSE177054 | GEO
Project description:Early-stage Luminal B breast cancer is frequent and is a major cause of breast cancer death due to its poor prognosis. Our proposal aims to study the biology behind the sensitivity and resistance of Luminal B breast cancer to chemotherapy (CHT) or a non-CHT regimen composed of hormone therapy in combination with ribociclib, a CDK4/6 inhibitor. To accomplish this, we first completed the SOLTI-1402 CORALLEEN phase II trial, a study where 106 patients with early-stage Luminal B breast cancer were randomized to standard neoadjuvant CHT for 6 months, or neoadjuvant letrozole and ribociclib for 6 months. After treatment, patients underwent surgery. The primary results of the study, which showed that the response rate to letrozole+ribociclib was similar to CHT, was reported (Prat et al; Lancet Oncol). Tumor biopsies were available at baseline, week 3 and surgery. A total of 257 samples were analyzed using the Illumina TruSeq Stranded Total RNA w/Ribo Zero Gold with MiSeq in TGL (Sequencer NovaSeq S4/PE/100x)
| EGAS00001007060 | EGA
Project description:Early-stage Luminal B breast cancer is frequent and is a major cause of breast cancer death due to its poor prognosis. Our proposal aims to study the biology behind the sensitivity and resistance of Luminal B breast cancer to chemotherapy (CHT) or a non-CHT regimen composed of hormone therapy in combination with ribociclib, a CDK4/6 inhibitor. To accomplish this, we first completed the SOLTI-1402 CORALLEEN phase II trial, a study where 106 patients with early-stage Luminal B breast cancer were randomized to standard neoadjuvant CHT for 6 months, or neoadjuvant letrozole and ribociclib for 6 months. After treatment, patients underwent surgery. The primary results of the study, which showed that the response rate to letrozole+ribociclib was similar to CHT, was reported (Prat et al; Lancet Oncol). Tumor biopsies were available at baseline, week 3 and surgery. A total of 257 samples were analyzed using the Illumina TruSeq Stranded Total RNA w/Ribo Zero Gold with MiSeq in TGL (Sequencer NovaSeq S4/PE/100x)
| EGAD00001010121 | EGA
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)
2015-07-06 | E-GEOD-59515 | biostudies-arrayexpress
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.
2015-07-06 | GSE59515 | GEO
Project description:In the present investigation, we have exploited the opportunity provided by neoadjuvant treatment of a group of postmenopausal women with large operable or locally advanced breast cancer (in which therapy is given with the primary tumour remaining within the breast) to take sequential biopsies of the same cancers before and after 10-14 days or 90 days treatment with letrozole. RNA extracted from the biopsies has been subjected to Affymetrix microarray analysis and the data from paired biopsies interrogated to discover genes whose expression is most influenced by oestrogen deprivation. Keywords: Timecourse between subjects
2010-07-28 | GSE20181 | GEO