Landscape of somatic mutations in different subtypes: Advanced breast cancer with circulating tumour DNA analysis.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e23039-e23039
Author(s):  
Zongbi Yi ◽  
Fei Ma ◽  
Yanfang Guan ◽  
Fang Li Yuan ◽  
Xiaoying Sun ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Regression Analysis ◽  
Advanced Breast Cancer ◽  
Endocrine Therapy ◽  
Somatic Mutations ◽  
Dna Analysis ◽  
Tumour Size ◽  
Multiple Logistic Regression Analysis ◽  
Genetic Alterations ◽  
Advanced Breast

e23039 Background: It is particularly important to provide precise therapies and understand tumor heterogeneity based on the molecular typing of gene expression. Yet the landscape of somatic mutations in different subtypes of advanced breast cancer (ABC) is largely undetermined. Methods: Overall, 100 blood samples were obtained from 100 advanced female breast cancer patients who underwent therapy at Cancer Hospital, Chinese Academy of Medical Sciences from March 2015 to September 2016. Mutations in 1021 tumor-related genes in ctDNA was assayed by gene-panel target-capture next-generation sequencing. Results: Somatic genomic alterations in ctDNA including copy number variants and point mutations were identified in 96 of 100 patients (96.0%). The number of somatic mutations varied markedly between individual patients (mean 2.9, range1-31). No difference was found between four subtypes for the number of somatic mutations. However, the mean number of somatic mutations was higher in age at 40-50 year than patients over age 60 ( p= 8.46 vs 3.88; p= 0.01). Results from multivariate analyses showed that the number of somatic mutations was increased with the number of endocrine therapy line ( p= 0.007). TP53 and PIK3CA were two most frequently mutated genes detected in ctDNA of 100 patients which were recurrently detected in 43 (43.0%) and 32 (32.0%) patients, respectively. ESR1/PIK3CA were more prevalent in HR+ cancers ( p= 0.007, 0.025 respectively). NOTCH1 are more frequently detected in HER2- group than in HER2+ patients (15.63% vs 2.94%; p= 0.033). In multiple logistic regression analysis indicated that pathological grade, tumour size at diagnosis and PR statue were positive associated with PIK3CA mutations. Multiple regression analysis also revealed that ki-67, metastatic at diagnosis, number of metastatic sites, number of endocrine line were associated with ESR1 mutations. Conclusions: The results revealed that different subtypes ABC have their own genetic alterations features. Certain gene mutations may be related to clinical treatment especially endocrine therapy.

scholarly journals Resistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2− Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5397
Author(s):  
Abeer J. Al-Qasem ◽  
Carla L. Alves ◽  
Henrik J. Ditzel
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Disease Progression ◽  
Endocrine Therapy ◽  
Combined Therapy ◽  
Predictive Biomarkers ◽  
Resistance Mechanisms ◽  
Genetic Alterations ◽  
Advanced Breast ◽  
Liquid Biopsies

The introduction of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) has revolutionized the treatment landscape for patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC) and has become the new standard treatment. However, resistance to this combined therapy inevitably develops and represents a major clinical challenge in the management of ER+ ABC. Currently, elucidation of the resistance mechanisms, identification of predictive biomarkers, and development of novel effective combined targeted treatments to overcome the resistance are active areas of research. Given the heterogeneity of the resistance mechanisms towards combined CDK4/6i and ET, identification of a single universal predictive biomarker of resistance is unlikely. Novel approaches are being explored, including examination of multiple genetic alterations in circulating cell-free tumor DNA in liquid biopsies from ABC patients with disease progression on combined CDK4/6i and ET treatment. Here, we review the molecular basis of the main known resistance mechanisms towards combined CDK4/6i and ET and associated potential biomarkers. As inhibiting key molecules in the pathways driving resistance may play an important role in the selection of therapeutic strategies for patients who experience disease progression on combined CDK4/6i and ET, we also review preclinical and early phase clinical data on novel combination therapies for these patients.

scholarly journals Circulating tumor DNA dynamics in advanced breast cancer treated with CDK4/6 inhibition and endocrine therapy

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Olga Martínez-Sáez ◽  
Tomás Pascual ◽  
Fara Brasó-Maristany ◽  
Nuria Chic ◽  
Blanca González-Farré ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Endocrine Therapy ◽  
Methodological Approach ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
Advanced Breast ◽  
Dna Dynamics ◽  
Ca 15.3 ◽  
Tumor Dna

AbstractCirculating tumor DNA (ctDNA) levels may predict response to anticancer drugs, including CDK4/6 inhibitors and endocrine therapy combinations (CDK4/6i+ET); however, critical questions remain unanswered such as which assay or statistical method to use. Here, we obtained paired plasma samples at baseline and week 4 in 45 consecutive patients with advanced breast cancer treated with CDK4/6i+ET. ctDNA was detected in 96% of cases using the 74-gene Guardant360 assay. A variant allele fraction ratio (VAFR) was calculated for each of the 79 detected mutations between both timepoints. Mean of all VAFRs (mVAFR) was computed for each patient. In our dataset, mVAFR was significantly associated with progression-free survival (PFS). Baseline VAF, on-treatment VAF or absolute changes in VAF were not associated with PFS, nor were CA-15.3 levels at baseline, week 4 or the CA-15.3 ratio. These findings demonstrate that ctDNA dynamics using a standardized multi-gene panel and a unique methodological approach predicts treatment outcome. Clinical trials in patients with an unfavorable ctDNA response are needed.

Cyclic Sequential Endocrine Therapy for Advanced Breast Cancer Using a Combination of Tamoxifen and Megestrol Acetate

Oncology ◽  
1994 ◽  
Vol 51 (1) ◽  
pp. 13-18 ◽  
Author(s):  
Derek J. Crawford ◽  
David George ◽  
David C. Smith ◽  
Moira Stewart ◽  
James Paul ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Endocrine Therapy ◽  
Advanced Breast ◽  
Megestrol Acetate ◽  
Sequential Endocrine Therapy

Everolimus and exemestane in hormone receptor-positive advanced breast cancer: A comprehensive cancer center’s experience.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13017-e13017
Author(s):  
Inês Moreira ◽  
Marta Ferreira ◽  
Ana Afonso ◽  
Ana Ferreira ◽  
Ana Rodrigues ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adverse Events ◽  
Advanced Breast Cancer ◽  
Endocrine Therapy ◽  
Hormone Receptor ◽  
Overall Response Rate ◽  
Response Rate ◽  
Advanced Breast ◽  
Overall Response ◽  
Hormone Receptor Positive

e13017 Background: Activation of the mammalian target of rapamycin intracellular signaling pathway is one of the mechanisms of endocrine resistance in breast cancer. The addition of everolimus to exemestane improves progression-free survival (PFS) in patients with hormone receptor positive (HR+) advanced breast cancer (ABC) previously treated with nonsteroidal aromatase inhibitors (NSAIs). The aim of this study was to assess the effectiveness and safety of everolimus plus exemestane in patients with HR+ ABC. Methods: We retrospectively evaluated patients with HR+, HER2 negative ABC treated with everolimus/exemestane that recurred or progressed during/after treatment with NSAIs in a portuguese comprehensive cancer center. Study endpoints were PFS, overall survival (OS), overall response rate and adverse events. Results: Between April 2014 and September 2020, 63 female patients were treated with everolimus/exemestane. Median age was 59 years (36-79), and all had performance status ECOG ≤2. Seventeen (27.0%) patients had bone metastasis alone, 39 (61.9%) had bone and visceral metastasis, 25 (39.7%) had metastasis in 3 or more sites and 87.3% had previous hormone-sensitive disease. Before everolimus/exemestane, 61 (96.8%) patients were being treated with palliative endocrine therapy (alone or in combination with CDK4/6 inhibitors) or chemotherapy (ChT) and 2 (3.2%) patients were under adjuvant endocrine therapy. Median follow-up time was 12.8 months (1.4-74.6), with 39 patients alive. Overall response rate was 14.3% (1 complete response and 8 partial responses) and 45 patients had stable disease. Median PFS was 5.6 months (CI95% 2.4-8.8) and median OS was 25.4 months (CI95% 10.3-40.5). Subgroup analysis regarding PFS was statistically significant for previous treatment with CDK4/6 inhibitors (p = 0.026) and for site of metastasis (p = 0.025). In the subgroup of patients that previously underwent palliative ChT, median PFS was 4.0 months (CI95% 0.2-9.6) and median OS was 18.6 months (CI95% 8.2-29.0). For patients that did not receive previous palliative ChT, median PFS was 5.8 months (CI95% 3.8-7.8) and median OS was 43.5 months (CI95% 2.0-85.0). Grade 3 and 4 adverse events occurred in 21 (33.3%) patients, and were: nausea, anorexia, rash, headache, haematologic toxicity, hepatic cytolysis, hyperglycaemia, pneumonitis, oral mucositis and acute kidney failure with need for haemodialysis. Fifty-five (87.3%) patients suspended everolimus, 34 (54.0%) due to disease progression and 21 (33.3%) due to toxicity. Conclusions: Our results confirm the effectiveness and safety of everolimus/exemestane in real-world setting and support its use mainly before palliative ChT. Everolimus/exemestane in HR+ ABC is feasible in the clinic, with toxicity manageable under close surveillance.

scholarly journals Currently Applied Molecular Assays for Identifying ESR1 Mutations in Patients with Advanced Breast Cancer

2020 ◽  
Vol 21 (22) ◽  
pp. 8807
Author(s):  
Nuri Lee ◽  
Min-Jeong Park ◽  
Wonkeun Song ◽  
Kibum Jeon ◽  
Seri Jeong
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Endocrine Therapy ◽  
High Sensitivity ◽  
Digital Pcr ◽  
Advanced Breast ◽  
Sample Type ◽  
Breast Cancers ◽  
Esr1 Mutations ◽  
Next Generation Sequencing Ngs

Approximately 70% of breast cancers, the leading cause of cancer-related mortality worldwide, are positive for the estrogen receptor (ER). Treatment of patients with luminal subtypes is mainly based on endocrine therapy. However, ER positivity is reduced and ESR1 mutations play an important role in resistance to endocrine therapy, leading to advanced breast cancer. Various methodologies for the detection of ESR1 mutations have been developed, and the most commonly used method is next-generation sequencing (NGS)-based assays (50.0%) followed by droplet digital PCR (ddPCR) (45.5%). Regarding the sample type, tissue (50.0%) was more frequently used than plasma (27.3%). However, plasma (46.2%) became the most used method in 2016–2019, in contrast to 2012–2015 (22.2%). In 2016–2019, ddPCR (61.5%), rather than NGS (30.8%), became a more popular method than it was in 2012–2015. The easy accessibility, non-invasiveness, and demonstrated usefulness with high sensitivity of ddPCR using plasma have changed the trends. When using these assays, there should be a comprehensive understanding of the principles, advantages, vulnerability, and precautions for interpretation. In the future, advanced NGS platforms and modified ddPCR will benefit patients by facilitating treatment decisions efficiently based on information regarding ESR1 mutations.

Sign in / Sign up

Export Citation Format

Share Document