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      Impact of DNA damage repair defects and aggressive variant features on response to carboplatin‐based chemotherapy in metastatic castration‐resistant prostate cancer

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          Platinum‐based chemotherapy is not standard of care for unselected or genetically selected metastatic castration‐resistant prostate cancer (mCRPC) patients. A retrospective assessment of 71 patients was performed on platinum use in the Netherlands. Genetically unselected patients yielded low response rates. For a predefined subanalysis of all patients with comprehensive next‐generation sequencing, 30 patients were grouped based on the presence of pathogenic aberrations in genes associated with DNA damage repair (DDR) or aggressive variant prostate cancer (AVPC). Fourteen patients (47%) were DDR deficient (DDRd), of which seven with inactivated BRCA2 (BRCA2mut). Six patients classified as AVPC. DDRd patients showed beneficial biochemical response to carboplatin, largely driven by all BRCA2mut patients having >50% prostate‐specific antigen (PSA) decline and objective radiographic response. In the wild‐type BRCA2 subgroup, 35% had a >50% PSA decline ( P = .006) and 16% radiographic response ( P < .001). Median overall survival was 21 months for BRCA2mut patients vs 7 months ( P = .041) for those with functional BRCA2. AVPC patients demonstrated comparable responses to non‐AVPC, including a similar overall survival, despite the poor prognosis for this subgroup. In the scope of the registration of poly‐(ADP)‐ribose polymerase inhibitors (PARPi) for mCRPC, we provide initial insights on cross‐resistance between PARPi and platinum compounds. By combining the literature and our study, we identified 18 patients who received both agents. In this cohort, only BRCA2mut patients treated with platinum first (n = 4), responded to both agents. We confirm that BRCA2 inactivation is associated with meaningful responses to carboplatin, suggesting a role for both PARPi and platinum‐based chemotherapy in preselected mCRPC patients.


          What's new?

          Platinum‐based chemotherapy is not standard of care for unselected or genetically‐selected patients with metastatic castration‐resistant prostate cancer (mCRPC). However, several studies have shown that platinum‐based chemotherapy may still have a role in postponing progression in selected patient groups. This new study investigating DNA damage repair gene alterations and response to platinum‐based chemotherapy provides evidence that deep and durable responses are primarily associated with patients harbouring BRCA2 inactivation. Based on these data and the limited available literature, platinum‐based chemotherapy followed by PARP inhibition is potentially emerging as the optimal treatment sequence in pre‐selected mCRPC patients.

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          Most cited references 33

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          New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

          Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.
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            The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer.

            DNA damage is a key factor both in the evolution and treatment of cancer. Genomic instability is a common feature of cancer cells, fuelling accumulation of oncogenic mutations, while radiation and diverse genotoxic agents remain important, if imperfect, therapeutic modalities. Cellular responses to DNA damage are coordinated primarily by two distinct kinase signaling cascades, the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. Historically, these pathways were thought to act in parallel with overlapping functions; however, more recently it has become apparent that their relationship is more complex. In response to DSBs, ATM is required both for ATR-Chk1 activation and to initiate DNA repair via homologous recombination (HRR) by promoting formation of single-stranded DNA at sites of damage through nucleolytic resection. Interestingly, cells and organisms survive with mutations in ATM or other components required for HRR, such as BRCA1 and BRCA2, but at the cost of genomic instability and cancer predisposition. By contrast, the ATR-Chk1 pathway is the principal direct effector of the DNA damage and replication checkpoints and, as such, is essential for the survival of many, although not all, cell types. Remarkably, deficiency for HRR in BRCA1- and BRCA2-deficient tumors confers sensitivity to cisplatin and inhibitors of poly(ADP-ribose) polymerase (PARP), an enzyme required for repair of endogenous DNA damage. In addition, suppressing DNA damage and replication checkpoint responses by inhibiting Chk1 can enhance tumor cell killing by diverse genotoxic agents. Here, we review current understanding of the organization and functions of the ATM-Chk2 and ATR-Chk1 pathways and the prospects for targeting DNA damage signaling processes for therapeutic purposes. Copyright © 2010 Elsevier Inc. All rights reserved.
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              Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results.

              Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk. (c) 2008 Wiley-Liss, Inc.

                Author and article information

                Int J Cancer
                Int J Cancer
                International Journal of Cancer
                John Wiley & Sons, Inc. (Hoboken, USA )
                03 October 2020
                15 January 2021
                : 148
                : 2 ( doiID: 10.1002/ijc.v148.2 )
                : 385-395
                [ 1 ] Department of Medical Oncology Radboud University Medical Center Nijmegen The Netherlands
                [ 2 ] Department of Urology Radboud University Medical Center Nijmegen The Netherlands
                [ 3 ] Institute for Medical Technology Assessment (iMTA), Erasmus School of Health Policy and Management Erasmus University Rotterdam Rotterdam The Netherlands
                [ 4 ] Department of Internal Medicine Amphia Hospital Breda The Netherlands
                [ 5 ] Department of Human Genetics Radboud University Medical Center Nijmegen The Netherlands
                [ 6 ] Department of Pathology Radboud University Medical Center Nijmegen The Netherlands
                [ 7 ] Department of Experimental Urology, Radboud Institute for Molecular Life Sciences Radboud University Medical Center Nijmegen The Netherlands
                Author notes
                [* ] Correspondence

                Niven Mehra, Department of Medical Oncology, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.

                Email: niven.mehra@ 123456radboudumc.nl

                © 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                Page count
                Figures: 4, Tables: 2, Pages: 11, Words: 7756
                Funded by: Radboudumc, Nijmegen, The Netherlands , open-funder-registry 10.13039/501100006209;
                Cancer Genetics and Epigenetics
                Cancer Genetics and Epigenetics
                Custom metadata
                15 January 2021
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:23.12.2020


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