^
2d
Furthermore, the majority of familiar pancreatic cancers could also be found in this latter subgroup. Unfortunately, the G12C mutation of KRAS in pancreatic cancer is rare, therefore pancreatic cancer patients could not benefit from the recent revolution of KRAS target therapies.
Journal • Tumor Mutational Burden • IO biomarker
|
KRAS (KRAS proto-oncogene GTPase) • TMB (Tumor Mutational Burden)
|
KRAS mutation • TMB-H • KRAS G12C • DDR • KRAS G12
2d
Furthermore, we demonstrate that tumors harboring biallelic RAD51B alteration are deficient in homologous recombination DNA repair deficiency (HRD), as evidenced by analysis of sequencing data and in vitro functional assays. Our findings suggest that RAD51B should be considered as an addition to clinical germline testing panels for breast and ovarian cancer susceptibility.
Journal
|
RAD51B (RAD51 Paralog B) • RAD51 (RAD51 Homolog A) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D)
|
DDR • RAD51D mutation • RAD51C mutation • RAD51 mutation
9d
In summary, we here identify SLF2 as a novel tumor suppressor of B-cell lymphomagenesis and link SLF2 deficiency to defective DNA repair. Moreover, we reveal the potential application of pharmacological inhibitors of the SUMOylation in a subgroup of B-cell lymphoma patients characterized by low SLF2 expression.
CHEK1 (Checkpoint kinase 1)
|
DDR
1m
We observed that CPT-CEF exerts its effect by possibly affecting the DNA repair mechanism through epigenetic modulation involving genes of HMGB1, APEX1, and POLE3. Hence, we propose that CPT-CEF could be a DNA repair modulator that harnesses the cell's epigenomic plasticity to amend DNA repair deficiencies in cancer cells.
Journal
|
HMGB1 (High Mobility Group Box 1)
|
DDR
2ms
This study provides evidence for the usefulness of HRD analysis in all cancer types, improves chemotherapy decision making and its efficacy in clinical settings, and represents a substantial advancement in precision oncology.A comprehensive pan-cancer analysis on the clinical significance of homologous recombination deficiency.
Journal • BRCA Biomarker
|
TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency)
|
TP53 mutation • BRCA2 mutation • HRD • DDR • TP53 expression
2ms
The combination of radiation and chemotherapy resulted in a better survival rate than chemotherapy alone in patients with an RNF8/CDH1 index. Taken together, the RNF8/CDH1 index not only functions as a prognostic and therapeutic marker but may also act as a target in the development of anti-cancer agents for patients with TNBC.
Clinical • Journal
|
CDH1 (Cadherin 1)
|
DDR • CDH1 expression
3ms
Senescence was the major cell death mechanism in p53 cells via p21-dependent pathway. Taken together, p21-mediated premature senescence might be used by tumor cells to escape from CIR-induced cytotoxicity, at least for a time.
Journal
|
CHEK2 (Checkpoint kinase 2) • CHEK1 (Checkpoint kinase 1) • TP53BP1 (Tumor Protein P53 Binding Protein 1) • CDKN1A (Cyclin-dependent kinase inhibitor 1A)
|
DDR
3ms
Somatic loss of wild-type CHEK2 gene copy is observed in about half of breast tumors arising in carriers of truncating CHEK2 mutations. Unlike BRCA1/2-associated BC, most of CHEK2-related neoplasms do not show the genomic signs of homologous DNA repair deficiency.
BRCA Biomarker
|
TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • CHEK2 (Checkpoint kinase 2) • BRCA (Breast cancer early onset)
|
TP53 mutation • BRCA1 mutation • BRCA2 mutation • PIK3CA mutation • DDR • CHEK2 mutation • BRCA mutation
4ms
CNV regions identified were not strongly associated with canonical ovarian cancer biological pathways, identifying candidates for future mechanistic investigations. External validation of the CNV risk score, especially in concert with more extensive clinical features, could be pursued via existing FDA-approved assays.
Clinical • Journal • Tumor Mutational Burden • BRCA Biomarker
|
TMB (Tumor Mutational Burden) • BRCA (Breast cancer early onset)
|
DDR • BRCA mutation
4ms
Additional signatures also play a role in colorectal cancer, including those related to normal aging and those associated with gut microbiota, as well as a number of signatures with unknown etiologies. This chapter provides an overview of the current knowledge of mutational signatures, with a focus on colorectal cancer and on the recently reported signatures in physiologically normal and inflammatory bowel disease-affected somatic colon tissues.
Journal
|
MSI (Microsatellite instability) • POLD1 (DNA Polymerase Delta 1) • MUTYH (MutY homolog)
|
DDR • POLD1 mutation
5ms
Integrated analysis of serial plasma samples from patients treated with PARP inhibition showed complex ATM copy number status within aneuploid genomics likely incongruent with DNA repair deficiency and loss of BRCA2 through germline and somatic signals. Conclusion Allele-informed analysis enabled by the PCF-SELECT assay shows benefit both for the sensitivity of detection and characterization of mPC genomic lesions from liquid biopsies.
Clinical • BRCA Biomarker • PARP Biomarker
|
BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • RB1 (RB Transcriptional Corepressor 1)
|
DDR
5ms
Integrated analysis of serial plasma samples from patients treated with PARP inhibition showed complex ATM copy number status within aneuploid genomics likely incongruent with DNA repair deficiency and loss of BRCA2 through germline and somatic signals. Conclusion Allele-informed analysis enabled by the PCF-SELECT assay shows benefit both for the sensitivity of detection and characterization of mPC genomic lesions from liquid biopsies.
Clinical • BRCA Biomarker • PARP Biomarker
|
BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • RB1 (RB Transcriptional Corepressor 1)
|
DDR
5ms
Integrated analysis of serial plasma samples from patients treated with PARP inhibition showed complex ATM copy number status within aneuploid genomics likely incongruent with DNA repair deficiency and loss of BRCA2 through germline and somatic signals. Conclusion Allele-informed analysis enabled by the PCF-SELECT assay shows benefit both for the sensitivity of detection and characterization of mPC genomic lesions from liquid biopsies.
Clinical • BRCA Biomarker • PARP Biomarker
|
BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • RB1 (RB Transcriptional Corepressor 1)
|
DDR
5ms
Integrated analysis of serial plasma samples from patients treated with PARP inhibition showed complex ATM copy number status within aneuploid genomics likely incongruent with DNA repair deficiency and loss of BRCA2 through germline and somatic signals. Conclusion Allele-informed analysis enabled by the PCF-SELECT assay shows benefit both for the sensitivity of detection and characterization of mPC genomic lesions from liquid biopsies.
Clinical • BRCA Biomarker • PARP Biomarker
|
BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • RB1 (RB Transcriptional Corepressor 1)
|
DDR
5ms
NBS1 overexpression reversed the effect of siRNA targeting MYC on glioma cells. MYC silencing inhibited the DNA damage response via regulation of NBS1, leading to DNA repair deficiency, and subsequently enhanced the sensitivity of glioma cells to HSYA.
Journal • PARP Biomarker • IO biomarker
|
MYC (V-myc avian myelocytomatosis viral oncogene homolog) • BCL2 (B-cell CLL/lymphoma 2) • CDH1 (Cadherin 1) • MRE11A (MRE11 homolog, double strand break repair nuclease) • RAD50 (RAD50 Double Strand Break Repair Protein)
|
DDR • MYC overexpression • BCL2 expression • MYC expression • CDH1 expression • ATM overexpression • BAX expression • ATM expression
6ms
Pembrolizumab was evaluated in a phase III, open-label, multicentre, randomised trial versus standard of care (SOC: FOLFOX6/FOLFIRI alone or in combination with bevacizumab/cetuximab) as first-line treatment of locally confirmed mismatch repair-deficient or microsatellite instability-high stage IV CRC. This is the first time the CHMP has issued an opinion for a target population defined by DNA repair deficiency biomarkers. The aim of this manuscript is to summarise the scientific review of the application leading to regulatory approval in the European Union.
Clinical • Review • Journal • Mismatch repair • Microsatellite instability • MSi-H Biomarker • PD(L)-1 Biomarker
|
MSI (Microsatellite instability)
|
MSI-H/dMMR • DDR
|
Keytruda (pembrolizumab) • Avastin (bevacizumab) • Erbitux (cetuximab)
6ms
Correlative aims include assessing blood and tissue biomarkers (e.g . PARP1, p65, phosphor-p65, let-7a miRNA, NF-kB, ctDNA, etc.) for association with clinical benefit and to predict response to therapy.
Clinical • P1/2 data • Combination therapy • BRCA Biomarker • PARP Biomarker
|
HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRCA (Breast cancer early onset)
|
BRCA1 mutation • BRCA2 mutation • HER-2 overexpression • DDR
|
Herceptin (trastuzumab) • Zejula (niraparib)
6ms
Finally, we found olaparib (PARPi; P = 0.002), GS-626510 (C-MYC/BETi; P < 0.000001 and P = 0.0005), and copanlisib (PIK3CAi; P = 0.0001) monotherapy to significantly inhibit uLMS-PDXs harboring derangements in C-MYC and PTEN/PIK3CA/AKT genes (LEY11) and/or HRD signatures (LEY16) compared to vehicle-treated mice. These findings define the genetic landscape of uLMS and suggest that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs.
Journal • PARP Biomarker
|
ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MSI (Microsatellite instability) • PTEN (Phosphatase and tensin homolog) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • RB1 (RB Transcriptional Corepressor 1) • ATRX (ATRX Chromatin Remodeler) • PARP1 (Poly(ADP-Ribose) Polymerase 1) • DAXX (Death-domain associated protein) • MAP2K4 (Mitogen-Activated Protein Kinase Kinase 4)
|
TP53 mutation • PTEN mutation • DDR • ALK fusion
|
Lynparza (olaparib) • Aliqopa (copanlisib) • GS-626510
6ms
We also recommend that olaparib or rucaparib be considered relatively early in the treatment sequence in metastatic castration-resistant prostate cancer patients with BRCA1 or BRCA2 mutations. Other DNA alterations might also sensitize to PARPi though the response rates are lower, so other standard therapies should be prioritized first.
Journal • BRCA Biomarker • PARP Biomarker
|
BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency)
|
BRCA1 mutation • BRCA2 mutation • HRD • DDR • HRD + BRCA1 mutation
|
Lynparza (olaparib) • Rubraca (rucaparib)
7ms
Cediranib and olaparib combination did not result in clinically meaningful activity in patients with mPDAC without gBRCAmt.
Clinical • Journal • BRCA Biomarker • PARP Biomarker
|
BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • RAD51 (RAD51 Homolog A) • BRCA (Breast cancer early onset)
|
DDR • BRCA1 expression • BRCA mutation • BRCA2 expression
|
Lynparza (olaparib) • Recentin (cediranib)
7ms
Our findings will decipher the role of DNA damage in BRCA1/2 mutated tumor cells and immune cell types. Outcomes can potentially predict treatment responses such as DNA damage, PARPi and checkpoint inhibitor therapies in TNBC BRCA1/2 breast cancer.
BRCA Biomarker • PARP Biomarker
|
BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • CD8 (cluster of differentiation 8) • GZMA (Granzyme A) • LAMP1 (Lysosomal Associated Membrane Protein 1)
|
BRCA1 mutation • BRCA2 mutation • DDR • High HRD score
7ms
In Cox proportional hazard multivariate analyses with covariates of age, stage, gender, HRD, and TP53 mutation, HRD was a good prognostic factor in the group with DNA-damaging agents, but a poor one in the group without the agents.&lsqb;Conclusion] Increased attention on locus-specific LOH in HRR pathway gene alterations and the differences in genomic scar signatures stratified by gender and TP53 mutation is newly warranted in order to properly assess HRD in a pan-cancer manner. The results in the present study proved the clinical significance of HRD across cancer types and may contribute to the development of personalized medicine based on HRD.
Clinical • BRCA Biomarker • PARP Biomarker • Pan tumor
|
TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency)
|
TP53 mutation • HRD • DDR
8ms
Clinical • New P2 trial • Pan tumor
|
HER-2 (Human epidermal growth factor receptor 2) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • ARID1A (AT-rich interaction domain 1A) • PBRM1 (Polybromo 1) • CDK12 (Cyclin dependent kinase 12) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • CHEK2 (Checkpoint kinase 2) • FANCA (FA Complementation Group A) • RAD51 (RAD51 Homolog A) • RAD51C (RAD51 paralog C) • RAD51D (RAD51 paralog D) • ARID2 (AT-Rich Interaction Domain 2) • RAD54L (DNA Repair And Recombination Protein RAD54) • BARD1 (BRCA1 Associated RING Domain 1) • NBN (Nibrin Nijmegen Breakage Syndrome 1 (Nibrin))
|
HER-2 positive • HER-2 amplification • DDR • CDK12 mutation • PBRM1 mutation • BRIP1 mutation • RAD51D mutation • CHEK2 mutation • RAD51C mutation • FANCA mutation • BARD1 mutation • NBN mutation
|
Zejula (niraparib) • Jemperli (dostarlimab)
8ms
Age-related alterations in TNBC, as well as breast cancer in general, need to be viewed in the context of underlying genomic phenotypes. Based on this notion, age at diagnosis alone does not appear to provide an additional layer of biological complexity above that of proposed genetic and transcriptional phenotypes of TNBC. Consequently, treatment decisions should be less influenced by age and more driven by tumor biology.
Clinical • Journal • Tumor Mutational Burden • BRCA Biomarker • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • AR (Androgen receptor) • CD20 (Membrane Spanning 4-Domains A1)
|
PIK3CA mutation • DDR
8ms
Our findings provide evidence that HDAC8 inhibition- or shSIRT6-induced DNA repair deficiencies are potently synergistic with NAMPT targeting, with minimal toxicity towards normal cells, providing a rationale for a novel-novel combination-based treatment for AML.
Journal
|
PARP1 (Poly(ADP-Ribose) Polymerase 1) • NAMPT (Nicotinamide Phosphoribosyltransferase) • SIRT6 (Sirtuin 6)
|
DDR
|
KPT-9274 • CRA-026440 • REC-2282
9ms
Although A+nP was more efficacious in patients with richer tumor immune microenvironment, clinical benefit was only observed in patients whose tumors were PD-L1 IC+.S.
Journal • BRCA Biomarker • PD(L)-1 Biomarker • IO biomarker
|
PD-L1 (Programmed death ligand 1) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • CD8 (cluster of differentiation 8) • BRCA (Breast cancer early onset)
|
PD-L1 expression • BRCA1 mutation • BRCA2 mutation • DDR • PD-L1 mutation • TILs
|
Tecentriq (atezolizumab) • Abraxane (albumin-bound paclitaxel)
9ms
We have established PDX from two HRD uLMS cases, enabling an evidence-based approach for testing PARPi combination therapies for these patients. Our work has provided support for screening for HRD in uLMS and a new avenue of therapeutic options for patients with this rare cancer type.
BRCA Biomarker • PARP Biomarker
|
BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset)
|
BRCA1 mutation • BRCA2 mutation • DDR
10ms
PARP inhibitors represent a safe and efficacious treatment for a subset of PDAC patients with BRCA mutations. Ongoing trials are evaluating PARP inhibitors in PDAC patients with non-BRCA DDR gene deficiencies as well as PARP inhibitors in combination with other agents, notably immune checkpoint inhibitors to expand the group of patients that derive benefit from this treatment.
Review • Journal • BRCA Biomarker • PARP Biomarker • IO biomarker
|
PALB2 (Partner and localizer of BRCA2) • BRCA (Breast cancer early onset)
|
ATM mutation • DDR • PALB2 mutation
10ms
The utility of our method was further shown by considering the detection of mismatch repair deficiency (MMRD) in gastric cancer, yielding an AUC = 0.81. Our results demonstrate the capacity of our learning-base system as a low-cost tool for DRD detection.
Journal
|
HRD (Homologous Recombination Deficiency)
|
HRD • DDR
11ms
This work contributes to the elucidation of the global molecular alterations of TNBC by providing accurate genomic data that may help forthcoming studies to improve treatment and survival. This is the first study that integrates genomic alterations with a long follow-up of clinical variables in a Latin American population that is an underrepresented ethnicity in most of the genomic studies.
Clinical • Journal • BRCA Biomarker
|
TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog) • CDKN1B (Cyclin dependent kinase inhibitor 1B)
|
TP53 mutation • BRCA1 mutation • BRCA2 mutation • PIK3CA mutation • PTEN mutation • DDR • BRCA1 mutation + BRCA2 mutation
11ms
The ATM-CHK2 and ATR-CHK1-WEE1 pathways initiate DNA DSB repair. In the current review, we focus on major DDR associated kinases including ATM, ATR, CHK1, CHK2, and WEE1, and discuss their potential prognostic and predictive value in solid malignancies.
Review • Journal • Tumor Mutational Burden • PARP Biomarker
|
TMB (Tumor Mutational Burden) • CHEK2 (Checkpoint kinase 2) • CTLA4 (Cytotoxic T-Lymphocyte Associated Protein 4) • ATR (Ataxia telangiectasia and Rad3-related protein)
|
TMB-H • DDR
11ms
Alterations of chromatin regulation have consequences for transcription factors that regulate expression of DNA repair genes. Under conditions where DNA repair is enhanced, induction chemotherapy was 78% less likely to effect remission in (-7) AML patients undergoing induction chemotherapy. Loss of H3K27 methylation associated with loss of PRC2 function by any means resulted in HOXA-upregulation and upregulation of DNA repair genes induced resistance to induction therapy.
Clinical
|
IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • DNMT3A (DNA methyltransferase 1) • HRD (Homologous Recombination Deficiency) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • ASXL1 (ASXL Transcriptional Regulator 1) • IKZF1 (IKAROS Family Zinc Finger 1) • KMT2C (Lysine Methyltransferase 2C) • PMS2 (PMS1 protein homolog 2) • CARD11 (Caspase Recruitment Domain Family Member 11) • HOXA9 (Homeobox A9) • DNMT3B (DNA Methyltransferase 3 Beta)
|
IDH1 mutation • DDR • DNMT3A mutation
12ms
iHRD is more accurate in identifying mCRPC tumors with functional HRD and predicting responses to therapeutics that exploit HRD.Funding Acknowledgments: DOD W81XWH-17-1-0380 and 2019 Roxann Taylor, Michael Deaddio, & Thomas H. Lee – PCF VAlor Young Investigator Award
PARP Biomarker
|
HRD (Homologous Recombination Deficiency) • CHEK2 (Checkpoint kinase 2) • MUS81 (MUS81 Structure-Specific Endonuclease Subunit)
|
TP53 mutation • HRD • DDR
|
carboplatin
12ms
In this review, we examine the current evidence for several prognostic, predictive and diagnostic tissue-based molecular biomarkers in prostate cancer management. For each assay, we summarize a recent survey of the International Society of Urology Pathology (ISUP) members on current testing practices and include recommendations for testing that emerged from the ISUP Working Group on Molecular Pathology of Prostate Cancer and the 2019 Consultation Conference on Molecular Pathology of Urogenital Cancers.
Journal • BRCA Biomarker
|
BRCA2 (Breast cancer 2, early onset) • PTEN (Phosphatase and tensin homolog)
|
DDR • PTEN loss
1year
The distinct histologic components of MBCs and UCSs were clonally related in all cases, with the sarcoma component likely stemming from a minor subclone of the carcinoma component in the samples with interpretable chronology of clonal evolution. Despite the similar histologic features and pathways affected by genetic alterations, UCSs differ from MBCs on the basis of FBXW7 and PPP2R1A mutations, HER2 amplification and lack of HRD, supporting the notion that these entities are more than mere phenocopies of the same tumor type in different anatomical sites.
Journal
|
HER-2 (Human epidermal growth factor receptor 2) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • FBXW7 (F-Box And WD Repeat Domain Containing 7) • FAT1 (FAT atypical cadherin 1)
|
HER-2 amplification • DDR
1year
Emerging methods to predict HRD, including genomic and functional assays, may overcome some of these challenges. Evaluation of HRD in the clinical setting is an important tool that has potential to aid patient selection for PARPi and other DNA-damaging agents in ovarian cancer, but understanding the details of these tests and their limitations is critical to ensure their optimal clinical application.
Clinical • Review • Journal • BRCA Biomarker • PARP Biomarker
|
BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset)
|
BRCA1 mutation • BRCA2 mutation • DDR • HRD + BRCA1 mutation
1year
BRCA-related DNA repair deficiency and suppressed tumor immune responses may be clinically relevant predictors of endocrine therapy complementing treatment options in subgroups of hormone-sensitive early breast cancer.
Clinical • Journal • Tumor Mutational Burden • BRCA Biomarker
|
HER-2 (Human epidermal growth factor receptor 2) • TMB (Tumor Mutational Burden) • PGR (Progesterone receptor) • AR (Androgen receptor) • BRCA (Breast cancer early onset)
|
HR positive • DDR • PGR positive • BRCA mutation • TILs
|
tamoxifen
1year
Pre-specified biomarker analysis was performed to test 7 immune genes/signatures previously associated with response to pembrolizumab [Pembro] and/or durvalumab and a DNA Repair Deficiency (DRD) signature previously associated with response to veliparib/carboplatin, as specific predictors of response to durvalumab/olaparib [Durva]. Multiple immune, DRD, proliferation, and ER signatures associate with response to durvalumab/olaparib therapy, but many lack predictive specificity. MP2 class and/or low ESR1/PGR are the strongest predictors of pCR in the HR+/HER2- subset; whereas for TNs, cytokine- and monocyte-dominated immune signatures like STAT1 [PMID: 19272155] and TAM/TcClassII ratio [PMID: 24205370] are most predictive of response. These results require validation.
Clinical • PD(L)-1 Biomarker • PARP Biomarker • IO biomarker
|
HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • CD68 (CD68 Molecule)
|
DDR
|
MammaPrint
|
Keytruda (pembrolizumab) • Lynparza (olaparib) • carboplatin • Imfinzi (durvalumab) • veliparib (ABT-888)
1year
Yet, other signaling pathways including epidermal growth factor receptor, RAS, Fyn, or p16INK4a signaling may play significant roles in squamous cell carcinoma development. The improved understanding of the molecular events leading to different tumor entities by de-differentiation of the same cell type has begun to pave the way for modulating new molecular targets therapeutically with small molecules.
Review • Journal
|
EGFR (Epidermal growth factor receptor) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • SMO (Smoothened Frizzled Class Receptor)
|
TP53 mutation • DDR
1year
TMB, BRCA1/2 mutations, and HRD are not associated with response or survival, cautioning against their use as selection criteria for ICI in recurrent OC. FGA should be investigated further as a biomarker of response to immunotherapy in OC.
Journal • Checkpoint inhibition • Tumor Mutational Burden • BRCA Biomarker
|
TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • BRCA (Breast cancer early onset)
|
BRCA1 mutation • BRCA2 mutation • DDR • BRCA mutation
1year
A subset of gBRCA1/2-associated ECs harbor biallelic BRCA1/2 alterations and genomic features of HRD, which may benefit from homologous recombination-directed treatment regimens. ECs in BRCA2 mutation carriers might be sporadic and even MSI high, and may potentially benefit from immune-checkpoint inhibition.
Journal • BRCA Biomarker • MSi-H Biomarker
|
TP53 (Tumor protein P53) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • MLH1 (MutL homolog 1)
|
TP53 mutation • BRCA1 mutation • BRCA2 mutation • MSI-H/dMMR • DDR • BRCA1 mutation + BRCA2 mutation
1year
E.g., ALK- or ROS1-rearrangements are common in inflammatory myofibroblastic tumors and permit treatment with tyrosine kinase inhibitors (TKI) such as crizotinib or lorlatinib...Recently, the NTRK-TKI larotrectinib has been approved for tumor-agnostic treatment of any NTRK-rearranged malignancy. MDM2-amplified liposarcomas are CDK4-co-amplified permitting targeted treatment with inhibitors such as palbociclib...For example tumor mutational burden (TMB) is predictive for response to immune checkpoint inhibitors (ICI) such as pembrolizumab, which has been recently approved for any malignancy with a TMB >10 mutations / Mb...Patients with such an aberration in their tumor tissue might benefit from inhibitors of poly-ADP-ribose-polymerase (PARP), similar to breast or ovarian cancer with mutations in BRCA or other genes provoking HRD. In summary, we will discuss the potential benefits and limitations of CGP in STS patients and discuss in the outlook potential ways of improving diagnostic profiling of STS beyond CGP.
Tumor Mutational Burden • BRCA Biomarker • PARP Biomarker • PD(L)-1 Biomarker • IO biomarker
|
ALK (Anaplastic lymphoma kinase) • TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • CDK4 (Cyclin-dependent kinase 4) • BRCA (Breast cancer early onset) • NTRK (Neurotrophic receptor tyrosine kinase)
|
TMB-H • ALK rearrangement • DDR • ROS1 rearrangement • CDK4 amplification • BRCA mutation • NTRK fusion
|
Keytruda (pembrolizumab) • Xalkori (crizotinib) • Vitrakvi (larotrectinib) • Ibrance (palbociclib) • Lorbrena (lorlatinib)
1year
The Pancreas Cancer Olaparib Ongoing (POLO) trial, in which olaparib as a maintenance treatment improved progression-free survival compared with placebo after platinum-based induction chemotherapy in patients with PDAC and germline BRCA1/2 mutations, raised great hopes of a substantially improved outcome for this patient subgroup. This review summarises the relationship between DDR and PDAC, the prevalence and characteristics of DNA repair mutations and options for the clinical management of patients with PDAC and DNA repair deficiency.
Review • Journal • BRCA Biomarker • PARP Biomarker
|
BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • PALB2 (Partner and localizer of BRCA2)
|
BRCA2 mutation • DDR
|
Lynparza (olaparib)
1year
In ad hoc analysis, rucaparib induced expression of interferon response genes in HR-deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors.
Clinical Trial,Phase II • Journal • PARP Biomarker
|
RAD51 (RAD51 Homolog A)
|
DDR
|
Rubraca (rucaparib)
1year
Legal entity responsible for the study: Third Hospital Peking University. Funding: Has not received any funding.
Tumor Mutational Burden • BRCA Biomarker
|
TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency)
|
BRCA2 mutation • HRD • DDR
1year
Legal entity responsible for the study: O. Cussenot. Funding: Myriad Genetics, Inc.
Tumor Mutational Burden • BRCA Biomarker
|
TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • BRCA2 (Breast cancer 2, early onset) • MSI (Microsatellite instability) • HRD (Homologous Recombination Deficiency) • CDK12 (Cyclin dependent kinase 12)
|
TP53 mutation • BRCA2 mutation • HRD • DDR • CDK12 mutation
1year
Legal entity responsible for the study: The authors. Funding: Chinese Academy of Medical Sciences.
Clinical • BRCA Biomarker
|
BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • HRD (Homologous Recombination Deficiency) • BRIP1 (BRCA1 Interacting Protein C-terminal Helicase 1) • RAD51D (RAD51 paralog D) • BRCA (Breast cancer early onset)
|
BRCA1 mutation • BRCA2 mutation • DDR • BRIP1 mutation • RAD51D mutation • BRCA mutation • RAD51 mutation
over1year
The deleterious mutations of PALB2 closely related to homologous recombination deficiency or alterations of DNA damage response and repair genes might be promising biomarkers for predicting efficacy of immune checkpoint inhibitors in pancreatic adenocarcinoma. Genetic correlation behind immunotherapy-induced systemic lupus erythematosus and associated mechanism remain to be elucidated.
Journal • PD(L)-1 Biomarker
|
HRD (Homologous Recombination Deficiency) • PALB2 (Partner and localizer of BRCA2) • Cancer antigen 19-9
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HRD • DDR • PALB2 mutation
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Keytruda (pembrolizumab)
over1year
Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA. These results provide a mechanistic rationale for directing SPA therapy to PCs with AR amplification or DNA repair deficiency, and for combining SPA therapy with PARP inhibition.
Journal • BRCA Biomarker • PARP Biomarker
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BRCA2 (Breast cancer 2, early onset) • AR (Androgen receptor)
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DDR • AR amplification
over1year
The addition of carboplatin to anthracycline, cyclophosphamide, and taxane (ACT) regimen is associated with improved complete pathologic response (pCR). Other targets, such as poly-ADP-ribosyl polymerase inhibitors (PARPi) and Phosphatidylinositol-3-kinase/Protein Kinase B/mammalian target of rapamycin (PI3K-AKT-mTOR) pathway inhibitors, are being evaluated in the neoadjuvant setting. This review examines recent progress in neoadjuvant therapy of TNBC, including platinum, ICI, PARPi, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) pathway targeted therapies, and novel tumor microenvironment (TME) targeted therapy, in addition to biomarkers for the prediction of pCR.
Clinical • Review • Journal • PARP Biomarker
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PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha)
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DDR • TILs
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carboplatin • cyclophosphamide intravenous
over1year
The reason of the inactivation of this pathway remains uncertain for most cases, even in the presence of a HR-deficient signature. Evidence indicates that identifying the mechanism of HR inactivation should improve both genetic counseling and therapeutic response, since they can be useful as new biomarkers of response.
Review • Journal • BRCA Biomarker
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset)
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BRCA1 mutation • BRCA2 mutation • DDR
over1year
This has led to early stage clinical trials of multiple PARP inhibitors (PARPi) for AML patients. Despite small patient numbers, evidence of modest clinical efficacy and tolerability in combinatorial regimens support the further development of PARP inhibition as a novel therapeutic strategy for AML, particularly in select molecular subsets (MLL rearranged, FLT3 and IDH1 mutant disease.
Review • Journal • BRCA Biomarker • PARP Biomarker
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IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • BRCA (Breast cancer early onset)
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DDR • BRCA mutation
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Lynparza (olaparib) • Talzenna (talazoparib)
over1year
Women who have pathogenic BRCA mutations are more likely to lose ovarian reserve after chemotherapy treatment, suggesting an emphasis on fertility preservation. Furthermore, our findings generate the hypothesis that DNA repair deficiency is a shared mechanism between aging, infertility, and cancer.
Clinical • Journal • BRCA Biomarker
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BRCA (Breast cancer early onset)
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DDR • BRCA mutation
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paclitaxel • doxorubicin hydrochloride • cyclophosphamide intravenous
over1year
Objective: The phase 3 VELIA trial demonstrated that veliparib dosed concurrently with carboplatin/paclitaxel and continued as maintenance monotherapy resulted in a statistically significant improvement in progression-free survival compared to carboplatin/paclitaxe alone in patients with newly diagnosed stage III–IV high-grade serous ovarian, fallopian tube, and peritoneal cancer. In VELIA, adverse event frequencies were generally similar among the whole patient population and biomarkerpositive patient subsets.
Clinical • Combination therapy • BRCA Biomarker • PARP Biomarker
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BRCA (Breast cancer early onset)
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DDR • BRCA mutation
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carboplatin • paclitaxel • veliparib (ABT-888)
over1year
Grade III ER+HER2- tumors have distinct clinical and molecular characteristics compared to grade I/II tumors, particularly with respect to non-luminal subgroup, and we should tailor and escalate therapies for them.Legal entity responsible for the study: Kang Wang. Funding: Has not received any funding.
Clinical
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • IL17A (Interleukin 17A) • CDKN1B (Cyclin dependent kinase inhibitor 1B) • GATA3 (GATA binding protein 3)
|
TP53 mutation • ER positive • DDR • MSLN positive
over1year
Grade III ER+HER2- tumors have distinct clinical and molecular characteristics compared to grade I/II tumors, particularly with respect to non-luminal subgroup, and we should tailor and escalate therapies for them.Legal entity responsible for the study: Kang Wang. Funding: Has not received any funding.
Clinical
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HER-2 (Human epidermal growth factor receptor 2) • ER (Estrogen receptor) • TP53 (Tumor protein P53) • IL17A (Interleukin 17A) • CDKN1B (Cyclin dependent kinase inhibitor 1B) • GATA3 (GATA binding protein 3)
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TP53 mutation • ER positive • DDR • MSLN positive
over1year
Treatment included durvalumab 1500 mg every 4 weeks x 3, olaparib 100 mg twice daily through weeks 1-11 concurrent with paclitaxel 80 mg/m2 weekly x 12 (DOP) followed by doxorubicin/cyclophosphamide (AC) x 4... I-SPY2 demonstrated a significant improvement in pCR with durvalumab and olaparib included with paclitaxel compared to chemotherapy alone in women with stage II/III high-risk, HER2-negative breast cancer, improvement was seen in both the HR+ and TNBC subsets.
Combination therapy • BRCA Biomarker • PARP Biomarker • PD(L)-1 Biomarker • IO biomarker
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HER-2 (Human epidermal growth factor receptor 2) • BRCA (Breast cancer early onset)
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PD-L1 expression • DDR
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Lynparza (olaparib) • paclitaxel • Imfinzi (durvalumab) • doxorubicin hydrochloride • cyclophosphamide intravenous
over1year
While in ovarian and prostate carcinomas both germinal and somatic, in breast and pancreatic cancers exclusively germinal, and in uterine sarcomas mostly somatic mutations specify the tumor as BRCA-dependent; platinum-sensitivity in ovarian cancer may replace BRCA testing by indicating the presence of frequent DNA repair deficiency. Platinum-based chemotherapy is frequently efficient in BRCA-dependent cancers, while PARP inhibitors yet registered for ovarian, breast and pancreatic cancers bring paradigm change in the treatment of ovarian cancer and provide an additional treatment option of the others.
Review • Journal • BRCA Biomarker • PARP Biomarker
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BRCA (Breast cancer early onset)
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DDR • BRCA mutation
over1year
Next-generation antiandrogens act through inhibiting androgen synthesis (abiraterone) or blocking ligand binding (enzalutamide). Selective targeting of PARP-2, however, may provide an alternative therapeutic approach for AR inhibition by disruption of FOXA1 function, which may be beneficial to patients, irrespective of their DNA-repair deficiency status.
Journal • PARP Biomarker
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AR (Androgen receptor)
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DDR • AR positive
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Xtandi (enzalutamide) • abiraterone acetate
over1year
The focused TST170 panel identified variants of potential clinical significance in the majority of patients analyzed. Of 14 patients, 10 had alterations within HRD genes potentially relevant for PARPi selection; however, only the 4 germline BRCA1 or BRCA2 mutations were clearly pathogenic for loss of BRCA function. The agreement between TST170 and WES indicated robust performance of both assays on these patient samples.
Clinical • Next-generation sequencing • BRCA Biomarker • PARP Biomarker
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • FGFR1 (Fibroblast growth factor receptor 1) • NOTCH2 (Notch 2) • BRCA (Breast cancer early onset)
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BRCA1 mutation • BRCA2 mutation • DDR • BRCA mutation • FGFR3 amplification
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Esclim (estradiol)
over1year
The focused TST170 panel identified variants of potential clinical significance in the majority of patients analyzed. Of 14 patients, 10 had alterations within HRD genes potentially relevant for PARPi selection; however, only the 4 germline BRCA1 or BRCA2 mutations were clearly pathogenic for loss of BRCA function. The agreement between TST170 and WES indicated robust performance of both assays on these patient samples.
Clinical • Next-generation sequencing • BRCA Biomarker • PARP Biomarker
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BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • FGFR1 (Fibroblast growth factor receptor 1) • NOTCH2 (Notch 2) • BRCA (Breast cancer early onset)
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BRCA1 mutation • BRCA2 mutation • DDR • BRCA mutation • FGFR3 amplification
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Esclim (estradiol)
over1year
The focused TST170 panel identified variants of potential clinical significance in the majority of patients analyzed. Of 14 patients, 10 had alterations within HRD genes potentially relevant for PARPi selection; however, only the 4 germline BRCA1 or BRCA2 mutations were clearly pathogenic for loss of BRCA function. The agreement between TST170 and WES indicated robust performance of both assays on these patient samples.
Clinical • Next-generation sequencing • BRCA Biomarker • PARP Biomarker
|
BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • FGFR1 (Fibroblast growth factor receptor 1) • NOTCH2 (Notch 2) • BRCA (Breast cancer early onset)
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BRCA1 mutation • BRCA2 mutation • DDR • BRCA mutation • FGFR3 amplification
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Esclim (estradiol)
over1year
The focused TST170 panel identified variants of potential clinical significance in the majority of patients analyzed. Of 14 patients, 10 had alterations within HRD genes potentially relevant for PARPi selection; however, only the 4 germline BRCA1 or BRCA2 mutations were clearly pathogenic for loss of BRCA function. The agreement between TST170 and WES indicated robust performance of both assays on these patient samples.
Clinical • Next-generation sequencing • BRCA Biomarker • PARP Biomarker
|
BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • FGFR1 (Fibroblast growth factor receptor 1) • NOTCH2 (Notch 2) • BRCA (Breast cancer early onset)
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BRCA1 mutation • BRCA2 mutation • DDR • BRCA mutation • FGFR3 amplification
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Esclim (estradiol)
over1year
Strikingly, further diminution of the vulnerable LXR-SREBF1-PNKP signaling pathway using a small molecule triptonide, a new LXR antagonist identified in this investigation, at a concentration of 8 nM robustly activated tumor-suppressor p53 and readily elevated cancer cell DNA strand breaks over an apoptotic threshold, and selectively induced PC cell apoptosis, resulting in almost complete elimination of tumors in xenograft mice without obvious complications. Our findings provide new insight into DNA repair and apoptosis in cancer, and offer a new platform for developing novel anticancer therapeutics.
Journal
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TP53 (Tumor protein P53)
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DDR
over1year
Transcriptome and DNA methylome analyses confirm epithelial-mesenchymal transition as a mechanism of sarcoma differentiation. The current study thus provides therapeutic possibilities for CS as well as clues to understanding the molecular histogenic mechanism of its development.
Clinical • Journal
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MSI (Microsatellite instability) • POLE (DNA Polymerase Epsilon)
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DDR • POLE mutation
over1year
The BRCAness of surgical specimens was found to be an important marker to predict prognosis in patients with TNBC after neoadjuvant chemotherapy. A clinical trial to assess the clinical impact of carboplatin with BRCAness is planned.
Retrospective data • Journal • BRCA Biomarker
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BRCA1 (Breast cancer 1, early onset)
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DDR
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carboplatin
over1year
We demonstrated that clinical PARPi, including olaparib and rucaparib, have cell-autonomous immunomodulatory properties in ERCC1-defective NSCLC and BRCA1-defective triple-negative breast cancer (TNBC) cells. PARPi also potentiated interferon-γ-induced PD-L1 expression in NSCLC cell lines and in fresh patient tumor cells; this effect was enhanced in ERCC1-deficient contexts. Our data provide the preclinical rationale for using PARPi as immunomodulatory agents in appropriately molecularly-selected populations.
Journal • BRCA Biomarker • PARP Biomarker • PD(L)-1 Biomarker
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PD-L1 (Programmed death ligand 1) • BRCA1 (Breast cancer 1, early onset) • ERCC1 (Excision repair cross-complementation group 1) • CCL5 (Chemokine (C-C motif) ligand 5)
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PD-L1 expression • BRCA1 mutation • DDR
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Lynparza (olaparib) • Rubraca (rucaparib)
over1year
PC patients carrying ≥1 pathogenic DNA instability mutation, and DRD mutation carriers specifically, had higher clinical burden than non-mutation carriers. Targeted therapies for these patients are needed to reduce clinical burden and associated healthcare resource utilization.
Clinical data • Retrospective data • Journal
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TP53 (Tumor protein P53) • PTEN (Phosphatase and tensin homolog) • RB1 (RB Transcriptional Corepressor 1)
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PTEN mutation • DDR
over1year
Objective: The phase 3 VELIA trial demonstrated that veliparib dosed concurrently with carboplatin/paclitaxel and continued as maintenance monotherapy resulted in a statistically significant improvement in progression-free survival compared to carboplatin/paclitaxe alone in patients with newly diagnosed stage III–IV high-grade serous ovarian, fallopian tube, and peritoneal cancer. In VELIA, adverse event frequencies were generally similar among the whole patient population and biomarker-positive patient subsets.
Clinical • Combination therapy • BRCA Biomarker • PARP Biomarker
|
BRCA (Breast cancer early onset)
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DDR • BRCA mutation
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carboplatin • paclitaxel • veliparib (ABT-888)
almost2years
Through synthetic lethal interactions, PARP inhibitors (PARPi) are currently used for the treatment of many solid tumors with underlying homologous recombination DNA repair deficiency. PARPi resistance is a common problem in the clinic, and multiple mechanisms of PARPi resistance have now been identified. As tumor cells acquire PARPi resistance, they may acquire new vulnerabilities. For instance, PARPi-resistant tumor cells may require alternative DNA repair pathways or a hyperactive ATR-CHK1-WEE1 pathway in order to survive. Targeting these alternative pathways is a new approach for overcoming PARPi resistance and for treating these tumors through drug combinations. The generation of targeted agents requires the use of novel DNA repair and cell cycle biomarkers as well as murine models and human organoid model systems.
PARP Biomarker
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ATR (Ataxia telangiectasia and Rad3-related protein) • CHEK1 (Checkpoint kinase 1)
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DDR