Mutations in BRCA2 and taxane resistance in prostate cancer

Nientiedt, Cathleen; Heller, Martina; Endris, Volker; Volckmar, Anna‐Lena; Zschäbitz, Stefanie; Tapia-Laliena, María Ángeles; Duensing, Anette; Jäger, Dirk; Schirmacher, Peter; Sültmann, Holger; Hohenfellner, Markus; Grüllich, Carsten; Duensing, Stefan

doi:10.1038/s41598-017-04897-x

Cited by 36 publications

(34 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A high pCR rate after neo-adjuvant anthracycline-taxane therapy was also demonstrated in BRCA1/2-mutated triple-negative breast cancer (n = 53) 240. Mutations in BRCA2 have a negative impact on the response rate to docetaxel in metastatic castration resistant prostate cancer (mCRPC) (n = 53) although no correlation was found between BRCA1/2 protein expression and response to treatment 241. Another large multi-institutional retrospective comparison of mCRPC patients (n = 390) with and without germline mutations in DNA repair genes (including BRCA2, ATM, CHEK2, BRCA1, PALB2, RAD51D and others) showed no difference between mutation carriers and non-carriers in their therapy response, progression-free survival after docetaxel or anti-androgen treatment and overall survival 242.…”

Section: Perspectives For the Treatment Of Patients With Brca Mutationsmentioning

confidence: 99%

BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance

Gorodetska¹,

Kozeretska²,

Dubrovska³

2019

J. Cancer

162

143

View full text Add to dashboard Cite

Carcinogenesis is a multistep process, and tumors frequently harbor multiple mutations regulating genome integrity, cell division and death. The integrity of cellular genome is closely controlled by the mechanisms of DNA damage signaling and DNA repair. The association of breast cancer susceptibility genes BRCA1 and BRCA2 with breast and ovarian cancer development was first demonstrated over 20 years ago. Since then the germline mutations within these genes were linked to genomic instability and increased risk of many other cancer types. Genomic instability is an engine of the oncogenic transformation of non-tumorigenic cells into tumor-initiating cells and further tumor evolution. In this review we discuss the biological functions of BRCA1 and BRCA2 genes and the role of BRCA mutations in tumor initiation, regulation of cancer stemness, therapy resistance and tumor progression.

show abstract

Section: Perspectives For the Treatment Of Patients With Brca Mutationsmentioning

confidence: 99%

BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance

Gorodetska¹,

Kozeretska²,

Dubrovska³

2019

J. Cancer

162

143

View full text Add to dashboard Cite

show abstract

“…Library preparation and semiconductor sequencing was performed as described earlier (17,18). In short, for both panels amplicon libraries were prepared using two primer pools with 5/10 ng of DNA and the Ion AmpliSeq Library Kit v2.0 (Thermo Fisher Scientific), respectively.…”

Section: Brca1 Brca2 As Well As Atm Atr Bard1 Brip1 Chek1 Chekmentioning

confidence: 99%

Patients Resistant Against PSMA-Targeting α-Radiation Therapy Often Harbor Mutations in DNA Damage-Repair–Associated Genes

et al. 2019

Self Cite

View full text Add to dashboard Cite

Prostate-specific membrane antigen (PSMA) targeting alpha-radiation therapy (TAT) is an emerging treatment modality for metastatic castration-resistant prostate cancer. There is a subgroup of patients with poor response despite sufficient expression of PSMA in their tumors. The aim of this work was to characterize PSMA-TAT nonresponding lesions by targeted next-generation sequencing (tNGS). Methods: Out of 60 patients treated with 225 Ac-PSMA-617, we identified 10 patients that presented with a poor response despite sufficient tumor-uptake in PSMA-PET/CT. We were able to perform CT-guided biopsies with histologic validation of the non-responding lesions in seven of these non-responding patients. Specimens were analyzed by tNGS interrogating 37 DNA damage-repair associated genes. Results: In the seven tumor samples analyzed, we found a total of 15 whole-gene deletions, deleterious or presumably deleterious mutations affecting TP53 (n=3); CHEK2 (n=2), ATM (n=2); BRCA1, BRCA2, PALB2, MSH2, MSH6, NBN, FANCB and PMS1 (n=1 each). The average number of deleterious or presumably deleterious mutations was 2.2 (range, 0-6) per patient. In addition, several variants of unknown significance in ATM, BRCA1, MSH2, SLX4, ERCC-and various FANC-genes were detected. Conclusion: Patients with resistance to PSMA-TAT despite PSMA-positivity frequently harbor mutations in DNA-damage-repair and checkpoint genes. While the causal role of these alterations in the patient outcome remains to be determined, our findings encourage future studies combining PSMA-TAT and DNA-damage-repair targeting agents such as Poly(ADPribose)-Polymerase inhibitors.

show abstract

“…A cell-line study on BRCA2m and TP53 wt OC showed high sensitivity to taxanes and platinum agents [77] although the clinical relevance of these findings is unclear and with limited retrospective data available suggesting no difference in response according to BRCA1/2 status [97]. Retrospective studies do suggest lower response to taxanes in s BRCA2m prostate, and BRCA1m breast cancer patients [98,99]. The relationship between taxane sensitivity and BRCA m in OC requires further investigation.…”

Section: Treatment Of Ovarian Cancer and Implications Of Brca1/2 Statusmentioning

confidence: 99%

Tailoring Ovarian Cancer Treatment: Implications of BRCA1/2 Mutations

Madariaga

Lheureux

Oza

2019

Cancers

View full text Add to dashboard Cite

High grade serous ovarian cancer (HGSOC) is the most common epithelial ovarian cancer, harbouring more than 20% germline or somatic mutations in the tumour suppressor genes BRCA1 and BRCA2. These genes are involved in both DNA damage repair process via homologous recombination (HR) and transcriptional regulation. BRCA mutation confers distinct characteristics, including an increased response to DNA-damaging agents, such us platinum chemotherapy and poly-ADP ribose polymerase inhibitors (PARPi). However, several mechanisms of resistance to these agents have been described, including increased HR capacity through reverse BRCA mutations, non-homologous end-joint (NHEJ) repair alterations and drug efflux pumps. Current treatments of ovarian cancer including surgery, chemotherapy, targeted treatment and maintenance strategies, as well as resistance mechanisms will be reviewed, focusing on future trends with respect to BRCA mutation carriers.

show abstract

Mutations in BRCA2 and taxane resistance in prostate cancer

Cited by 36 publications

References 41 publications

BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance

BRCA Genes: The Role in Genome Stability, Cancer Stemness and Therapy Resistance

Patients Resistant Against PSMA-Targeting α-Radiation Therapy Often Harbor Mutations in DNA Damage-Repair–Associated Genes

Tailoring Ovarian Cancer Treatment: Implications of BRCA1/2 Mutations

Contact Info

Product

Resources

About