30 research outputs found
Moving From Poly (ADP-Ribose) Polymerase Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy
The DNA damage response (DDR) pathway coordinates the identification, signaling, and repair of DNA damage caused by endogenous or exogenous factors and regulates cell-cycle progression with DNA repair to minimize DNA damage being permanently passed through cell division. Severe DNA damage that cannot be repaired may trigger apoptosis; as such, the DDR pathway is of crucial importance as a cancer target. Poly (ADP-ribose) polymerase (PARP) is the best-known element of the DDR, and several PARP inhibitors have been licensed. However, there are approximately 450 proteins involved in DDR, and a number of these other targets are being investigated in the laboratory and clinic. We review the most recent evidence for the clinical effect of PARP inhibition in breast and ovarian cancer and explore expansion into the first-line setting and into other tumor types. We critique the evidence for patient selection techniques and summarize what is known about mechanisms of PARP inhibitor resistance. We then discuss what is known about the preclinical rationale for targeting other members of the DDR pathway and the associated tumor cell genetics that may confer sensitivity to these agents. Examples include DNA damage sensors (MLH1), damage signaling molecules (ataxia-telangiectasia mutated; ataxia-telangiectasia mutated–related and Rad3-related; CHK1/2; DNA-dependent protein kinase, catalytic subunit; WEE1; CDC7), or effector proteins for repair (POLQ [also referred to as POLθ], RAD51, poly [ADP-ribose] glycohydrolase). Early-phase clinical trials targeting some of these molecules, either as a single agent or in combination, are discussed. Finally, we outline the challenges that must be addressed to maximize the therapeutic opportunity that targeting DDR provides
Boosting care and knowledge about hereditary cancer: European Reference Network on Genetic Tumour Risk Syndromes
Approximately 27–36 million patients in Europe have one of the ~ 5.000–8.000 known rare diseases. These patients often
do not receive the care they need or they have a substantial delay from diagnosis to treatment. In March 2017, twenty-four
European Reference Networks (ERNs) were launched with the aim to improve the care for these patients through cross
border healthcare, in a way that the medical knowledge and expertise travels across the borders, rather than the patients.
It is expected that through the ERNs, European patients with a rare disease get access to expert care more often and more
quickly, and that research and guideline development will be accelerated resulting in improved diagnostics and therapies.
The ERN on Genetic Tumour Risk Syndromes (ERN GENTURIS) aims to improve the identification, genetic diagnostics,
prevention of cancer, and treatment of European patients with a genetic predisposition for cancer. The ERN GENTURIS
focuses on syndromes such as hereditary breast cancer, hereditary colorectal cancer and polyposis, neurofibromatosis and
more rare syndromes e.g. PTEN Hamartoma Tumour Syndrome, Li Fraumeni Syndrome and hereditary diffuse gastric cancer
Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk
BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat
Psychosocial impact of undergoing prostate cancer screening for men with BRCA1 or BRCA2 mutations.
OBJECTIVES: To report the baseline results of a longitudinal psychosocial study that forms part of the IMPACT study, a multi-national investigation of targeted prostate cancer (PCa) screening among men with a known pathogenic germline mutation in the BRCA1 or BRCA2 genes. PARTICPANTS AND METHODS: Men enrolled in the IMPACT study were invited to complete a questionnaire at collaborating sites prior to each annual screening visit. The questionnaire included sociodemographic characteristics and the following measures: the Hospital Anxiety and Depression Scale (HADS), Impact of Event Scale (IES), 36-item short-form health survey (SF-36), Memorial Anxiety Scale for Prostate Cancer, Cancer Worry Scale-Revised, risk perception and knowledge. The results of the baseline questionnaire are presented. RESULTS: A total of 432 men completed questionnaires: 98 and 160 had mutations in BRCA1 and BRCA2 genes, respectively, and 174 were controls (familial mutation negative). Participants' perception of PCa risk was influenced by genetic status. Knowledge levels were high and unrelated to genetic status. Mean scores for the HADS and SF-36 were within reported general population norms and mean IES scores were within normal range. IES mean intrusion and avoidance scores were significantly higher in BRCA1/BRCA2 carriers than in controls and were higher in men with increased PCa risk perception. At the multivariate level, risk perception contributed more significantly to variance in IES scores than genetic status. CONCLUSION: This is the first study to report the psychosocial profile of men with BRCA1/BRCA2 mutations undergoing PCa screening. No clinically concerning levels of general or cancer-specific distress or poor quality of life were detected in the cohort as a whole. A small subset of participants reported higher levels of distress, suggesting the need for healthcare professionals offering PCa screening to identify these risk factors and offer additional information and support to men seeking PCa screening
The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant
PURPOSE : To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score
(PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.
METHODS : We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402
prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2
(CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall
and ER-specific PRS313 and CBC risk.
RESULTS : For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard
ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive
PRS313, HR= 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological
characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative
PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes,
respectively.
CONCLUSION : The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the
PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decisionmaking.This work was supported by the Alpe d’HuZes/Dutch Cancer Society (KWF
Kankerbestrijding) project 6253 and Dutch Cancer Society (KWF Kankerbestrijding)
project UL2014-7473. CIMBA: The CIMBA data management and data analysis were
supported by Cancer Research–UK grants C12292/A20861, C12292/A11174. G.C.T.
and A.B.S. are NHMRC Research Fellows. iCOGS: the European Community’s Seventh
Framework Programme under grant agreement number 223175 (HEALTH-F2-2009-
223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/
A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/
A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS
initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112–the GAME-ON
initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes
of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-
87521), and the Ministry of Economic Development, Innovation and Export Trade
(PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research
Foundation, and the Ovarian Cancer Research Fund. OncoArray: the PERSPECTIVE
and PERSPECTIVE I&I projects funded by the Government of Canada through
Genome Canada and the Canadian Institutes of Health Research, the Ministère de
l’Économie, de la Science et de l’Innovation du Québec through Genome Québec,
and the Quebec Breast Cancer Foundation; the NCI Genetic Associations and
Mechanisms in Oncology (GAME-ON) initiative and Discovery, Biology and Risk of
Inherited Variants in Breast Cancer (DRIVE) project (NIH grants U19 CA148065 and
X01HG007492); and Cancer Research UK (C1287/A10118 and C1287/A16563). BCFR:
UM1 CA164920 from the National Cancer Institute. The content of this paper does
not necessarily reflect the views or policies of the National Cancer Institute or any of
the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does
mention of trade names, commercial products, or organizations imply endorsement
by the US Government or the BCFR. BFBOCC: Lithuania (BFBOCC-LT): Research
Council of Lithuania grant SEN-18/2015. BIDMC: Breast Cancer Research Foundation.
BMBSA: Cancer Association of South Africa (PI Elizabeth J. van Rensburg). BRI-COH: S.
L.N. is partially supported by the Morris and Horowitz Families Professorship. CNIO:
Spanish Ministry of Health PI16/00440 supported by FEDER funds, the Spanish
Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER). COH-CCGCRN: Research
reported in this publication was supported by the National Cancer Institute of the
National Institutes of Health under grant number R25CA112486, and RC4CA153828
(PI: J. Weitzel) from the National Cancer Institute and the Office of the Director,
National Institutes of Health. The content is solely the responsibility of the authors
and does not necessarily represent the official views of the National Institutes of
Health. CONSIT TEAM: Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 number
16732) to P. Peterlongo. DEMOKRITOS: European Union (European Social Fund–ESF)
and Greek national funds through the Operational Program “Education and Lifelong
Learning” of the National Strategic Reference Framework (NSRF)–Research Funding
Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA.
Investing in knowledge society through the European Social Fund. DFKZ: German
Cancer Research Center. EMBRACE: Cancer Research UK Grants C1287/A10118 and
C1287/A11990. D.G.E. and F.L. are supported by an NIHR grant to the Biomedical
Research Centre, Manchester. The Investigators at The Institute of Cancer Research
and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the
Biomedical Research Centre at The Institute of Cancer Research and The Royal
Marsden NHS Foundation Trust. R.E. and E.B. are supported by Cancer Research UK
Grant C5047/A8385. R.E. is also supported by NIHR support to the Biomedical
Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC: A.K.G. was in part funded by the NCI (R01 CA214545), The
University of Kansas Cancer Center Support Grant (P30 CA168524), The Kansas
Institute for Precision Medicine (P20 GM130423), and the Kansas Bioscience Authority
Eminent Scholar Program. A.K.G. is the Chancellors Distinguished Chair in Biomedical
Sciences Professorship. FPGMX: A. Vega is supported by the Spanish Health Research
Foundation, Instituto de Salud Carlos III (ISCIII), partially supported by FEDER funds
through Research Activity Intensification Program (contract grant numbers: INT15/
00070, INT16/00154, INT17/00133), and through Centro de Investigación Biomédica
en Red de Enferemdades Raras CIBERER (ACCI 2016: ER17P1AC7112/2018);
Autonomous Government of Galicia (Consolidation and structuring program:
IN607B), and by the Fundación Mutua Madrileña. The German Consortium for
Hereditary Breast and Ovarian Cancer (GC-HBOC) is funded by the German Cancer
Aid (110837, 70111850, coordinator: Rita K. Schmutzler, Cologne) and the Ministry for
Innovation, Science and Research of the State of North Rhine-Westphalia (#323-
8.0302.16.02-132142). GEMO: initially funded by the French National Institute of
Cancer (INCa, PHRC Ile de France, grant AOR 01 082, 2001-2003, grant 2013-1-BCB-01-
ICH-1), the Association “Le cancer du sein, parlons-en!” Award (2004), the Association
for International Cancer Research (2008-2010), and the Foundation ARC pour la
recherche sur le cancer (grant PJA 20151203365). It also received support from the
Canadian Institute of Health Research for the “CIHR Team in Familial Risks of Breast
Cancer” program (2008–2013), and the European commission FP7, Project
«Collaborative Ovarian, breast and prostate Gene-environment Study (COGS),
Large-scale integrating project» (2009–2013). GEMO is currently supported by the
INCa grant SHS-E-SP 18-015. GEORGETOWN: The Survey, Recruitment, and Biospecimen
Collection Shared Resource at Georgetown University (NIH/NCI grant P30-
CA051008), the Fisher Center for Hereditary Cancer and Clinical Genomics Research,
and the Nina Hyde Center for Breast Cancer Research. G-FAST: Bruce Poppe is a
senior clinical investigator of FWO. Mattias Van Heetvelde obtained funding from
IWT. HCSC: Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301
CIBERONC from ISCIII (Spain), partially supported by European Regional Development
FEDER funds. HEBCS: Helsinki University Hospital Research Fund, the Finnish Cancer
Society and the Sigrid Juselius Foundation. The HEBON study is supported by the
Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organisation of Scientific Research grant NWO 91109024, the Pink
Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46
and the Transcan grant JTC 2012 Cancer 12-054. HRBCP: Hong Kong Sanatorium and
Hospital, Dr Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation,
National Institute of Health1R 03CA130065, and North California Cancer Center.
HUNBOCS: Hungarian Research Grants KTIA-OTKA CK-80745, NKFI_OTKA K-112228
and TUDFO/51757/2019-ITM. ICO: Contract grant sponsor: Supported by the Carlos III
National Health Institute funded by FEDER funds–a way to build Europe–(PI16/00563,
PI19/00553 and CIBERONC); the Government of Catalonia (Pla estratègic de recerca i
innovació en salut (PERIS) Project MedPerCan, 2017SGR1282 and 2017SGR496); and
CERCA program.IHCC: supported by grant PBZ_KBN_122/P05/2004 and the program
of the Minister of Science and Higher Education under the name “Regional Initiative
of Excellence” in 2019–2022 project number 002/RID/2018/19 amount of financing 12
000 000 PLN. ILUH: Icelandic Association “Walking for Breast Cancer Research” and by
the Landspitali University Hospital Research Fund. INHERIT: Canadian Institutes of
Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program–grant
CRN-87521 and the Ministry of Economic Development, Innovation and Export
Trade–grant # PSR-SIIRI-701. IOVHBOCS: Ministero della Salute and “5×1000” Istituto
Oncologico Veneto grant. IPOBCS: Liga Portuguesa Contra o Cancro. kConFab: The
National Breast Cancer Foundation, and previously by the National Health and
Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer
Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer
Foundation of Western Australia. KOHBRA: the Korea Health Technology R&D Project
through the Korea Health Industry Development Institute (KHIDI), and the National
R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea
(HI16C1127; 1020350; 1420190). KUMC: NIGMS P20 GM130423 (to A.K.G.). MAYO: NIH
grants CA116167, CA192393 and CA176785, an NCI Specialized Program of Research
Excellence (SPORE) in Breast Cancer (CA116201), and a grant from the Breast Cancer
Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast
Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade.
Marc Tischkowitz is supported by the funded by the European Union Seventh
Framework Program (2007Y2013)/European Research Council (Grant No. 310018).
MODSQUAD: MH CZ–DRO (MMCI, 00209805) and LM2018125, MEYS–NPS I–LO1413 to LF, and by Charles University in Prague project UNCE204024 (MZ). MSKCC: the
Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer
Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support
Grant/Core Grant (P30 CA008748). NAROD: 1R01 CA149429-01. NCI: the Intramural
Research Program of the US National Cancer Institute, NIH, and by support services
contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP-65504 with Westat, Inc,
Rockville, MD. NICCC: Clalit Health Services in Israel, the Israel Cancer Association and
the Breast Cancer Research Foundation (BCRF), NY. NNPIO: the Russian Foundation
for Basic Research (grants 17-00-00171, 18-515-45012 and 19-515-25001). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative
Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA
37517) and the Intramural Research Program, NCI. OSUCCG: Ohio State University
Comprehensive Cancer Center. PBCS: supported by the “Fondazione Pisa per la
Scienza, project nr. 127/2016. Maria A Caligo was supported by the grant: “n. 127/16
Caratterizzazione delle varianti missenso nei geni BRCA1/2 per la valutazione del
rischio di tumore al seno” by Fondazione Pisa, Pisa, Italy; SEABASS: Ministry of
Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/
06) and Cancer Research Initiatives Foundation. SMC: the Israeli Cancer Association.
SWE-BRCA: the Swedish Cancer Society. UCHICAGO: NCI Specialized Program of
Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996,
1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the
Entertainment Industry Fund National Women’s Cancer Research Alliance and the
Breast Cancer research Foundation. O.I.O. is an ACS Clinical Research Professor. UCLA:
Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research
Foundation. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive
Cancer Center. UKFOCR: Cancer Research h UK. UPENN: Breast Cancer Research
Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for
BRCA. UPITT/MWH: Hackers for Hope Pittsburgh. VFCTG: Victorian Cancer Agency,
Cancer Australia, National Breast Cancer Foundation. WCP: B.Y.K. is funded by the
American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and
the National Center for Advancing Translational Sciences (NCATS), grant
UL1TR000124.https://www.gimjournal.org/am2023Genetic
Phenotype comparison of MLH1 and MSH2 mutation carriers in a cohort of 1,914 individuals undergoing clinical genetic testing in the United States
Background and Aims: Lynch syndrome is caused by germ-line mismatch repair gene mutations. We examined the phenotypic differences between MLH1 and MSH2 gene mutation carriers and whether mutation type (point versus large rearrangement) affected phenotypic expression. Methods: This is a cross-sectional prevalence study of 1,914 unrelated probands undergoing clinical genetic testing for MLH1 and MSH2 mutations at a commercial laboratory. Results: Fifteen percent (285 of 1,914) of subjects had pathogenic mutations (112 MLH1, 173 MSH2). MLH1 carriers had a higher prevalence of colorectal cancer (79% versus 69%, P = 0.08) and younger mean age at diagnosis (42.2 versus 44.8 years, P = 0.03) than MSH2 carriers. Forty-one percent of female carriers had endometrial cancer and prevalence was similar in both groups. Other cancers were more frequent in MSH2 carriers (24% versus 9%, P = 0.001) and their families (P < 0.001). Multivariable analyses confirmed these associations. Of the 1,016 subjects who underwent Southern blot analysis, 42 had large rearrangements (7 MLH1, 35 MSH2). There were no phenotypic differences between carriers with large rearrangements and point mutations. Conclusions: In this large study of mismatch repair gene mutation carriers from the United States, MLH1 carriers had more colorectal cancer than MSH2 carriers whereas endometrial cancer prevalence was similar. Large genomic rearrangements were more frequent in the MSH2 gene. MSH2 carriers and their relatives have more extracolonic nonendometrial Lynch syndrome-associated cancers and may benefit from additional screening. Copyrigh
Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG)
Purpose PALB2 germline pathogenic variants are associated with increased breast cancer risk and smaller increased risk of pancreatic and likely ovarian cancer. Resources for health-care professionals managing PALB2 heterozygotes are currently limited. Methods A workgroup of experts sought to outline management of PALB2 heterozygotes based on current evidence. Peer-reviewed publications from PubMed were identified to guide recommendations, which arose by consensus and the collective expertise of the authors. Results PALB2 heterozygotes should be offered BRCA1/2-equivalent breast surveillance. Risk-reducing mastectomy can be considered guided by personalized risk estimates. Pancreatic cancer surveillance should be considered, but ideally as part of a clinical trial. Typically, ovarian cancer surveillance is not recommended, and risk-reducing salpingo-oophorectomy should only rarely be considered before the age of 50. Given the mechanistic similarities, PALB2 heterozygotes should be considered for therapeutic regimens and trials as those for BRCA1/2. Conclusion This guidance is similar to those for BRCA1/2. While the range of the cancer risk estimates overlap with BRCA1/2, point estimates are lower in PALB2 so individualized estimates are important for management decisions. Systematic prospective data collection is needed to determine as yet unanswered questions such as the risk of contralateral breast cancer and survival after cancer diagnosis
Comparison of the clinical prediction model PREMM1,2,6 and molecular testing for the systematic identification of Lynch syndrome in colorectal cancer
Background Lynch syndrome is caused by germline
mismatch repair (MMR) gene mutations. The
PREMM1,2,6 model predicts the likelihood of a MMR
gene mutation based on personal and family cancer
history.
Objective To compare strategies using PREMM1,2,6 and
tumour testing (microsatellite instability (MSI) and/or
immunohistochemistry (IHC) staining) to identify
mutation carriers.
Design Data from population-based or clinic-based
patients with colorectal cancers enrolled through the
Colon Cancer Family Registry were analysed. Evaluation
included MSI, IHC and germline mutation analysis for
MLH1, MSH2, MSH6 and PMS2. Personal and family
cancer histories were used to calculate PREMM1,2,6
predictions. Discriminative ability to identify carriers from
non-carriers using the area under the receiver operating
characteristic curve (AUC) was assessed. Predictions
were based on logistic regression models for (1) cancer
assessment using PREMM1,2,6, (2) MSI, (3) IHC for
loss of any MMR protein expression, (4) MSI+IHC,
(5) PREMM1,2,6+MSI, (6) PREMM1,2,6+IHC,
(7) PREMM1,2,6+IHC+MSI.
Results Among 1651 subjects, 239 (14%) had
mutations (90 MLH1, 125 MSH2, 24 MSH6).
PREMM1,2,6 discriminated well with AUC 0.90 (95% CI
0.88 to 0.92). MSI alone, IHC alone, or MSI+IHC each
had lower AUCs: 0.77, 0.82 and 0.82, respectively. The
added value of IHC+PREMM1,2,6 was slightly greater
than PREMM1,2,6+MSI (AUC 0.94 vs 0.93). Adding MSI
to PREMM1,2,6+IHC did not improve discrimination.
Conclusion PREMM1,2,6 and IHC showed excellent
performance in distinguishing mutation carriers from noncarriers and performed best when combined. MSI may
have a greater role in distinguishing Lynch syndrome
from other familial colorectal cancer subtypes among
cases with high PREMM1,2,6 scores where genetic
evaluation does not disclose a MMR mutation
Recommended from our members
Abstract CT007: PETRA: First in class, first in human trial of the next generation PARP1-selective inhibitor AZD5305 in patients (pts) with BRCA1/2, PALB2 or RAD51C/D mutations
Abstract
Background: AZD5305 is a potent, highly selective PARP1 inhibitor and trapper with superior preclinical tolerability, target engagement and efficacy vs 1st generation dual PARP1/2 inhibitors (PARPi). This is the first report of the ongoing Phase 1/2a PETRA (NCT04644068) trial.
Methods: Pts with advanced breast, ovarian, prostate or pancreatic cancer bearing germline or somatic BRCA1/2, PALB2 or RAD51C/D mutations received AZD5305 QD PO until disease progression. ECOG PS 0-2 and Hb ≥9.0 g/dL were required. Prior PARPi and platinum therapy were permitted. The primary objective was safety; secondary objectives included pharmacokinetics (PK) and pharmacodynamics in tumor and/or blood samples and response by RECIST v1.1, CA125 or PSA. Exploratory genomic analyses included zygosity evaluation and ctDNA response monitoring.
Results: At data cutoff (Nov 17, 2021), 46 pts received AZD5305 10-90 mg QD (43.5% had prior PARPi; median 3.5 prior lines of therapy). AZD5305 was well tolerated across all doses without DLTs (Table). PK exposures were dose-proportional. Steady-state Ctrough was higher than 1st generation PARPi: specifically 6.3 and 31.9 fold above target effective concentration at 10 and 90 mg, respectively. PARylation inhibition was ≥90% at 10-40 mg QD (PBMCs) confirming target engagement. 7/25 (28%) pts had objective responses: 5 RECIST PRs (3 confirmed) and 2 additional pts with PSA50 responses (1 confirmed), including platinum- and PARPi-resistant pts. 13/22 (59%) RECIST-measurable pts had SD or PR up to 51+ weeks. ctDNA declined on treatment in 7/13 (54%) evaluable pts (3 complete, 4 &gt;50% reductions) across doses.
Conclusions: AZD5305 is a highly selective PARP1 inhibitor and trapper with excellent physiochemical properties and a wide therapeutic index. It led to maximal target engagement and showed promising clinical activity with favorable tolerability at exposures surpassing those of 1st generation PARPi.
AZD5305 10 mg/d (n=8) AZD5305 20 mg/d (n=19) AZD5305 40 mg/d (n=13) AZD5305 60 mg/d (n=3) AZD5305 90 mg/d (n=3) Total (N=46) Most common (&gt;10%) TRAEs, n (%) Any grade Any grade Any grade Any grade Any grade Grade ≥3 Any grade Nausea 3 (37.5) 5 (26.3) 1 (7.7) 1 (33.3) 0 0 10 (21.7) Anemia* 2 (25.0) 4 (21.1) 1 (7.7) 0 0 6 (13.0) 7 (15.2) Neutropenia* 3 (37.5) 2 (10.5) 1 (7.7) 0 1 (33.3) 2 (4.3) 7 (15.2) Thrombocytopenia* 1 (12.5) 2 (10.5) 2 (15.4) 0 0 1 (2.2) 5 (10.9) Fatigue and asthenia* 2 (25.0) 2 (10.5) 0 1 (33.3) 0 0 5 (10.9) Any TRAE leading to dose reduction 1 (12.5) 0 0 0 0 1 (2.2) Any TRAE leading to discontinuation 0 0 0 0 0 0 AE, adverse event; TRAE, treatment-related adverse event *Grouped Terms
Citation Format: Timothy A. Yap, Seock-Ah Im, Alison M. Schram, Adam Sharp, Judith Balmana, Richard D. Baird, Jessica S. Brown, Maria Schwaederle, Elizabeth A. Pilling, Ganesh Moorthy, Spiros Linardopoulos, Adam Dowson, Carol Pound, Edit Lukacs, Sabina Cosulich, Stephen J. Luen. PETRA: First in class, first in human trial of the next generation PARP1-selective inhibitor AZD5305 in patients (pts) with BRCA1/2, PALB2 or RAD51C/D mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT007.</jats:p