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  1. Article ; Online: PARP inhibitors-understanding the risk of myelodysplastic syndrome and acute myeloid leukaemia.

    Tinker, Anna V

    The Lancet. Haematology

    2020  Volume 8, Issue 2, Page(s) e97–e99

    MeSH term(s) Humans ; Leukemia, Myeloid, Acute/drug therapy ; Myelodysplastic Syndromes/chemically induced ; Myelodysplastic Syndromes/drug therapy ; Pharmacovigilance ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Retrospective Studies ; World Health Organization
    Chemical Substances Poly(ADP-ribose) Polymerase Inhibitors
    Language English
    Publishing date 2020-12-18
    Publishing country England
    Document type Journal Article ; Comment
    ISSN 2352-3026
    ISSN (online) 2352-3026
    DOI 10.1016/S2352-3026(20)30375-6
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  2. Article: Omission of adjuvant therapy in stage I clear cell ovarian cancer: Review of the BC Cancer experience.

    Liu, Shiru L / Tinker, Anna V

    Gynecologic oncology reports

    2019  Volume 31, Page(s) 100533

    Abstract: Background: Since 2012, the BC Cancer provincial treatment guideline for surgically staged stage IA/B and IC1 (defined by intraoperative rupture only) clear cell ovarian cancer (CCOC) has been to offer observation only. We reviewed the clinical outcomes ...

    Abstract Background: Since 2012, the BC Cancer provincial treatment guideline for surgically staged stage IA/B and IC1 (defined by intraoperative rupture only) clear cell ovarian cancer (CCOC) has been to offer observation only. We reviewed the clinical outcomes of all stage I CCOC patients since policy implementation.
    Methods: A retrospective, population-based cohort study of all stage I CCOC patients operated on between April 2012 and December 2017 was conducted. Patient, tumor, surgical and clinical outcome data were collected. Survival analysis was conducted using Kaplan-Meier methods.
    Results: 78 patients with stage I disease were identified. 40 patients with stages IA/B and IC1, who underwent post-operative observation, were included in the analysis. Lymph node dissection was omitted in 20 patients (50%). Median duration of follow-up was 36 months. There were 4 recurrences (10%), 3 metastatic. The 5-year disease-free survival is 90%, and the 5-year overall survival is 95% for stage IA/B and 90% for stage IC1 (p = 0.645). In comparison, 5-year overall survival for stage IC2 (surface involvement) and IC1 with sharp dissection (all received adjuvant chemotherapy) is 82% (p < 0.001) and for stage IC3 (positive washings) was 23% (p < 0.001).
    Conclusion: Adjuvant therapy can be safely omitted in patients with stage I A/B and IC1 CCOC. Recurrence rates are low and survival is >90% at 5 years. Stage IC2 /IC3 had worse outcomes, thus stage I substage is instrumental in predicting clinical outcomes for CCOC. Lymph node metastases are rare in stage IA/B/C1 CCOC as absence of lymphadenectomy did not increase the risk of disease recurrence.
    Language English
    Publishing date 2019-12-29
    Publishing country Netherlands
    Document type Case Reports
    ZDB-ID 2818505-5
    ISSN 2352-5789
    ISSN 2352-5789
    DOI 10.1016/j.gore.2019.100533
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  3. Article: Fighting resistance: post-PARP inhibitor treatment strategies in ovarian cancer.

    Veneziani, Ana C / Scott, Clare / Wakefield, Matthew J / Tinker, Anna V / Lheureux, Stephanie

    Therapeutic advances in medical oncology

    2023  Volume 15, Page(s) 17588359231157644

    Abstract: Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a therapeutic milestone in the management of epithelial ovarian cancer. The concept of 'synthetic lethality' is exploited by PARPi in tumors with defects in DNA repair pathways, particularly ... ...

    Abstract Poly (ADP-ribose) polymerase inhibitors (PARPis) represent a therapeutic milestone in the management of epithelial ovarian cancer. The concept of 'synthetic lethality' is exploited by PARPi in tumors with defects in DNA repair pathways, particularly homologous recombination deficiency. The use of PARPis has been increasing since its approval as maintenance therapy, particularly in the first-line setting. Therefore, resistance to PARPi is an emerging issue in clinical practice. It brings an urgent need to elucidate and identify the mechanisms of PARPi resistance. Ongoing studies address this challenge and investigate potential therapeutic strategies to prevent, overcome, or re-sensitize tumor cells to PARPi. This review aims to summarize the mechanisms of resistance to PARPi, discuss emerging strategies to treat patients post-PARPi progression, and discuss potential biomarkers of resistance.
    Language English
    Publishing date 2023-03-01
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2503443-1
    ISSN 1758-8359 ; 1758-8340
    ISSN (online) 1758-8359
    ISSN 1758-8340
    DOI 10.1177/17588359231157644
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  4. Article ; Online: PARP Inhibitors and the Evolving Landscape of Ovarian Cancer Management: A Review.

    Cook, Sarah A / Tinker, Anna V

    BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy

    2019  Volume 33, Issue 3, Page(s) 255–273

    Abstract: As a drug class, inhibitors of poly-(ADP-ribose) polymerase (PARP) have had their greatest impact on the treatment of women with epithelial ovarian cancers (EOC), in particular, those with the most common histological subtype, high-grade serous cancer, ... ...

    Abstract As a drug class, inhibitors of poly-(ADP-ribose) polymerase (PARP) have had their greatest impact on the treatment of women with epithelial ovarian cancers (EOC), in particular, those with the most common histological subtype, high-grade serous cancer, as it has high rates of homologous recombination (HR) deficiency. PARP inhibition exploits this cancer vulnerability by further disrupting DNA repair, thus leading to genomic catastrophe. Early clinical data demonstrated the effectiveness of PARP inhibition in women with recurrent EOC harbouring BRCA1/2 mutations and those with platinum-sensitive recurrences. Three PARP inhibitors (olaparib, niraparib, and rucaparib) are now approved for use in women with recurrent EOC. Based upon randomised controlled trials, PARP inhibitors are in use as "maintenance" therapy for those with platinum-sensitive and platinum-responsive recurrences (irrespective of BRCA1/2 mutation status). Among women with BRCA1/2 mutations (either germline or somatic), maintenance PARP inhibitor therapy for those with recurrence has led to a nearly fourfold prolongation of progression-free survival compared to placebo control. Those without BRCA1/2 mutations experience an approximately twofold increase in progression-free survival. The latest clinical data demonstrate that women with BRCA1/2 mutations who respond to first-line chemotherapy and go on to have maintenance olaparib experience a doubling of the rate of freedom from death at 3 years when compared to placebo (60% vs 27%). PARP inhibitors are also approved as active therapy for women with germline or tumour BRCA1/2 mutations and recurrent EOC treated with three or more prior lines of therapy. Apart from the presence of a BRCA1/2 mutation (germline or somatic) and clinical factors such as platinum sensitivity and responsiveness, other predictive biomarkers are not in routine clinical use. Assays to identify genomic aberrations caused by HR deficiency, or mutations in genes involved in HR, have not been sufficiently sensitive to identify all patients who benefit from treatment. The mechanisms of PARP-inhibitor resistance include restoration of HR through reversion mutations in HR genes, capable of re-establishing the DNA open-reading frame and leading to resumed HR function. Other mechanisms that sustain sufficient DNA repair may also be important. This review focuses on the rationale for the use of PARP inhibitors in EOC. The data that have shaped clinical research are presented, and the trials that have changed management standards are reviewed and discussed. Highlighted are the past and ongoing efforts to further improve and explore the use of PARP inhibitors in EOC.
    MeSH term(s) Animals ; DNA Repair/drug effects ; Female ; Humans ; Mutation/drug effects ; Neoplasm Recurrence, Local/drug therapy ; Ovarian Neoplasms/drug therapy ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
    Chemical Substances Poly(ADP-ribose) Polymerase Inhibitors
    Language English
    Publishing date 2019-03-20
    Publishing country New Zealand
    Document type Journal Article ; Review
    ZDB-ID 1364202-9
    ISSN 1179-190X ; 1173-8804
    ISSN (online) 1179-190X
    ISSN 1173-8804
    DOI 10.1007/s40259-019-00347-4
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  5. Article: A rapidly evolving landscape: immune checkpoint inhibitors in pretreated metastatic endometrial cancer.

    Tinker, Anna V / Dhani, Neesha C / Ghatage, Prafull / McLeod, Deanna / Samouëlian, Vanessa / Welch, Stephen A / Altman, Alon D

    Therapeutic advances in medical oncology

    2023  Volume 15, Page(s) 17588359231157633

    Abstract: Background and objectives: Endometrial cancer is a common malignancy and recurrences can be fatal. Although platinum-pretreated endometrial tumors are commonly treated with anthracyclines and taxanes, there is no current standard of care. Both immune ... ...

    Abstract Background and objectives: Endometrial cancer is a common malignancy and recurrences can be fatal. Although platinum-pretreated endometrial tumors are commonly treated with anthracyclines and taxanes, there is no current standard of care. Both immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) have been extensively assessed in this setting, including tumors selected for DNA mismatch repair (MMR)/microsatellite instability (MSI) and programmed death-ligand 1 expression status. This review will provide evidence-based guidance on use of ICIs alone or in combination with TKIs in patients with pretreated advanced, persistent, or recurrent metastatic endometrial cancer.
    Data sources and methods: Randomized phase II-III trials in unselected populations pretreated, recurrent, or metastatic endometrial cancer and phase I-II trials in biomarker selected populations were identified from PubMed as well as conference proceedings using the key search terms 'immune checkpoint inhibitors', 'endometrial cancer', and 'advanced'.
    Results: A total of nine eligible studies were identified assessing ICI monotherapy for biomarker-selected or ICI plus TKI combinations and a dual ICI regimen for biomarker-unselected patients with pretreated recurrent or metastatic endometrial cancer. In MMR/MSI-selected tumors, five phase I/II studies evaluated ICI monotherapy indicating benefit in these patients. Only the phase III KEYNOTE-775 trial reported a statistically significant overall survival improvement for the combination of pembrolizumab plus lenvatinib compared with docetaxel or paclitaxel regardless of MMR/MSI status.
    Conclusions: Pembrolizumab plus lenvatinib is indicated for patients with unselected pretreated metastatic endometrial cancer and pembrolizumab monotherapy is a preferred option for patients with MMRd/MSI-H tumors.
    Language English
    Publishing date 2023-03-18
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2503443-1
    ISSN 1758-8359 ; 1758-8340
    ISSN (online) 1758-8359
    ISSN 1758-8340
    DOI 10.1177/17588359231157633
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  6. Article ; Online: Targeted Error-Suppressed Detection of Circulating Paternal DNA to Establish a Diagnosis of Gestational Trophoblastic Neoplasm.

    Lavoie, Jean-Michel / Alcaide, Miguel / Fisher, Rosemary A / Seckl, Michael J / Morin, Ryan / Tinker, Anna V

    JCO precision oncology

    2021  Volume 1, Page(s) 1–6

    Language English
    Publishing date 2021-12-31
    Publishing country United States
    Document type Journal Article
    ISSN 2473-4284
    ISSN (online) 2473-4284
    DOI 10.1200/PO.17.00154
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  7. Article ; Online: Germline Testing and Somatic Tumor Testing for <i>BRCA1/2</i> Pathogenic Variants in Ovarian Cancer: What Is the Optimal Sequence of Testing?

    Kwon, Janice S / Tinker, Anna V / Santos, Jennifer / Compton, Katie / Sun, Sophie / Schrader, Kasmintan A / Karsan, Aly

    JCO precision oncology

    2022  Volume 6, Page(s) e2200033

    Abstract: Purpose: In 2020, ASCO recommended that all women with epithelial ovarian cancer have germline testing for ... BRCA1/2 ... mutations, and those without a germline pathogenic variant (PV) should have somatic tumor testing to determine eligibility for a ... ...

    Abstract Purpose: In 2020, ASCO recommended that all women with epithelial ovarian cancer have germline testing for BRCA1/2 mutations, and those without a germline pathogenic variant (PV) should have somatic tumor testing to determine eligibility for a poly (ADP-ribose) polymerase inhibitor. Consequently, the majority of patients with ovarian cancer will have both germline testing and somatic testing. An alternate strategy is tumor testing first and then germline testing if there is a PV in the tumor and/or significant family history. The objective was to conduct a cost-effectiveness analysis comparing the two testing strategies.
    Methods: The Markov model compared the costs (US dollars) and benefits of two testing strategies for newly diagnosed ovarian cancer: (1) ASCO strategy and (2) tumor testing triage for germline testing. Data were applied from SOLO-1, and costs were from wholesale acquisition prices, Medicare, and published sources. Sensitivity analyses accounted for uncertainty around various parameters. Monte Carlo simulation estimated the number tested and identified with germline and somatic BRCA PV for olaparib maintenance treatment annually in the US population.
    Results: The ASCO strategy was more effective but more costly than tumor testing triage in identifying patients for olaparib, with an incremental cost-effectiveness ratio of $281,296 US dollars per progression-free life year gained. Assuming 10,000 eligible patients with ovarian cancer annually, Monte Carlo simulation yielded comparable numbers of patients with BRCA PV in the germline and tumor with the ASCO and tumor testing triage strategies (2,080 v 2,062, respectively), but substantially higher number of patients tested using the ASCO strategy (8,052 v 3,076).
    Conclusion: The ASCO strategy may identify more BRCA PVs but is not cost-effective. Tumor testing in epithelial ovarian cancer as triage for germline testing is the favored strategy in this health care system.
    MeSH term(s) Aged ; Female ; Humans ; Adenosine Diphosphate/therapeutic use ; Antineoplastic Agents ; BRCA1 Protein/genetics ; Carcinoma, Ovarian Epithelial/diagnosis ; Germ Cells/pathology ; Germ-Line Mutation/genetics ; Medicare ; Ovarian Neoplasms/diagnosis ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Ribose/therapeutic use ; United States
    Chemical Substances Adenosine Diphosphate (61D2G4IYVH) ; Antineoplastic Agents ; BRCA1 Protein ; BRCA1 protein, human ; Poly(ADP-ribose) Polymerase Inhibitors ; Ribose (681HV46001) ; BRCA2 protein, human
    Language English
    Publishing date 2022-10-19
    Publishing country United States
    Document type Journal Article
    ISSN 2473-4284
    ISSN (online) 2473-4284
    DOI 10.1200/PO.22.00033
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  8. Article ; Online: Treatment and outcomes in undifferentiated and dedifferentiated endometrial carcinoma.

    Hamilton, Sarah Nicole / Tinker, Anna V / Kwon, Janice / Lim, Peter / Kong, Iwa / Sihra, Sona / Koebel, Martin / Lee, Cheng Han

    Journal of gynecologic oncology

    2022  Volume 33, Issue 3, Page(s) e25

    Abstract: Objective: Undifferentiated and dedifferentiated endometrial carcinoma is a rare type of uterine malignancy. This study assesses disease characteristics, treatment and survival outcomes in patients with undifferentiated and dedifferentiated endometrial ... ...

    Abstract Objective: Undifferentiated and dedifferentiated endometrial carcinoma is a rare type of uterine malignancy. This study assesses disease characteristics, treatment and survival outcomes in patients with undifferentiated and dedifferentiated endometrial carcinoma treated at BC Cancer.
    Methods: All patients diagnosed with undifferentiated and dedifferentiated endometrial carcinoma between 2000 and 2019 at BC Cancer were reviewed centrally. Clinical, pathologic, treatment and outcomes were reviewed retrospectively. The Kaplan-Meier method was used to evaluate overall survival (OS) and disease-free survival (DFS). Multivariable analysis was performed using Cox regression analysis.
    Results: Fifty-two patients were included, 33% had undifferentiated carcinoma and 67% dedifferentiated carcinoma. Sixty-nine percent of those who had mismatch repair (MMR) testing of their tumor had an abnormal profile. The 5-year DFS was 80% (95% confidence interval [CI]=71%-89%) for stage I/II, 29% (95% CI=28%-40%) for stage III and 10% (95% CI 1%-19%) for stage IV. The 5-year OS was 84% (95% CI=75%-92%) for stage I/II, 38% (95% CI=26%-50%) for stage III and 12% (95% CI=1%-24%) for stage IV. Multivariate analysis showed that receiving adjuvant chemotherapy, adjuvant radiotherapy, lower stage and better Eastern Cooperative Group performance status were associated with improved DFS (p<0.05).
    Conclusion: Patients with stage I/II undifferentiated and dedifferentiated endometrial carcinoma had excellent survival outcomes, those with stage III/IV had worse outcomes, similar to previously reported. Adjuvant chemotherapy and radiotherapy were associated with improved DFS. MMR testing should be performed for these patients due to the high incidence of abnormal profiles.
    MeSH term(s) Carcinoma/drug therapy ; Chemotherapy, Adjuvant ; Disease-Free Survival ; Endometrial Neoplasms/pathology ; Female ; Humans ; Neoplasm Staging ; Radiotherapy, Adjuvant ; Retrospective Studies
    Language English
    Publishing date 2022-01-24
    Publishing country Korea (South)
    Document type Journal Article
    ZDB-ID 2478405-9
    ISSN 2005-0399 ; 2005-0380
    ISSN (online) 2005-0399
    ISSN 2005-0380
    DOI 10.3802/jgo.2022.33.e25
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    Zs.A 6484: Show issues Location:
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  9. Article ; Online: CD8 + T cell infiltration is associated with improved survival and negatively correlates with hypoxia in clear cell ovarian cancer.

    Guo, Nancy / Yang, Aijun / Farooq, Fabiha Binte / Kalaria, Shreena / Moss, Elena / DeVorkin, Lindsay / Lesperance, Mary / Bénard, François / Wilson, Don / Tinker, Anna V / Nathoo, Farouk S / Hamilton, Phineas T / Lum, Julian J

    Scientific reports

    2023  Volume 13, Issue 1, Page(s) 6530

    Abstract: Unlike other histological types of epithelial ovarian carcinoma, clear cell ovarian carcinoma (CCOC) has poor response to therapy. In many other carcinomas, expression of the hypoxia-related enzyme Carbonic anhydrase IX (CAIX) by cancer cells is ... ...

    Abstract Unlike other histological types of epithelial ovarian carcinoma, clear cell ovarian carcinoma (CCOC) has poor response to therapy. In many other carcinomas, expression of the hypoxia-related enzyme Carbonic anhydrase IX (CAIX) by cancer cells is associated with poor prognosis, while the presence of CD8 + tumor-infiltrating lymphocytes (TIL) is positively prognostic. We employed [
    MeSH term(s) Female ; Humans ; Antigens, Neoplasm/metabolism ; Biomarkers, Tumor/metabolism ; Canada ; Carbonic Anhydrase IX ; Carbonic Anhydrases/metabolism ; Hypoxia/pathology ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/pathology ; Positron Emission Tomography Computed Tomography ; Prognosis ; Lymphocytes, Tumor-Infiltrating ; CD8-Positive T-Lymphocytes
    Chemical Substances Antigens, Neoplasm ; Biomarkers, Tumor ; Carbonic Anhydrase IX (EC 4.2.1.1) ; Carbonic Anhydrases (EC 4.2.1.1)
    Language English
    Publishing date 2023-04-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-023-30655-3
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  10. Article ; Online: Bevacizumab in Metastatic, Recurrent, or Persistent Cervical Cancer: The BC Cancer Experience.

    Tinker, Anna V / Fiorino, Leathia / O'Dwyer, Helena / Kumar, Aalok

    International journal of gynecological cancer : official journal of the International Gynecological Cancer Society

    2018  Volume 28, Issue 8, Page(s) 1592–1599

    Abstract: Objective: We conducted a population-based analysis of patient outcomes following treatment with bevacizumab and platinum-based chemotherapy for metastatic, recurrent, or persistent cervical carcinoma.: Methods: Eligible cases were identified using ... ...

    Abstract Objective: We conducted a population-based analysis of patient outcomes following treatment with bevacizumab and platinum-based chemotherapy for metastatic, recurrent, or persistent cervical carcinoma.
    Methods: Eligible cases were identified using the BC Cancer provincial pharmacy database. Cases with small cell component or inadequate clinical follow-up were excluded. Overall response to therapy, progression-free survival (PFS), overall survival (OS), and toxicities were documented.
    Results: Twenty-seven eligible cases were included with a median follow-up of 12.1 months. The median age at recurrence/metastatic diagnosis was 49 years (range, 27-83 years). Twenty-three of 27 women received carboplatin, paclitaxel, and bevacizumab as first-line treatment, and 4 of 27 as second-line treatment. The median number of cycles of bevacizumab delivered was 5.5 (range, 1-21). The overall response rate was 44% (12/27), with 11% (3/27) complete response and 33% (9/27) partial response. Median PFS and OS for the entire cohort were 5.3 and 12.1 months, respectively. In first-line therapy, the median PFS and OS were 6.3 and 17.5 months, respectively. Common toxicities included anemia (grade 1/2) 73% (19/27), and the following grade 2 or greater: neutropenia 38% (n = 10) with 1 occurrence of febrile neutropenia, hypertension 30% (n = 8), and thrombosis 22% (n = 6). The fistula rate was 3.7% (n = 1).
    Conclusions: In this population-based analysis, the combination of bevacizumab and platinum-based chemotherapy as first-line therapy for metastatic, recurrent, or persistent cervical carcinoma was safely delivered and had outcomes comparable to results from the GOG 240 phase III trial.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Bevacizumab/administration & dosage ; Bevacizumab/adverse effects ; Carboplatin/administration & dosage ; Carboplatin/adverse effects ; Female ; Humans ; Middle Aged ; Neoplasm Metastasis ; Neoplasm Recurrence, Local/drug therapy ; Neoplasm Recurrence, Local/pathology ; Paclitaxel/administration & dosage ; Paclitaxel/adverse effects ; Progression-Free Survival ; Retrospective Studies ; Uterine Cervical Neoplasms/drug therapy ; Uterine Cervical Neoplasms/pathology
    Chemical Substances Bevacizumab (2S9ZZM9Q9V) ; Carboplatin (BG3F62OND5) ; Paclitaxel (P88XT4IS4D)
    Language English
    Publishing date 2018-09-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 1070385-8
    ISSN 1525-1438 ; 1048-891X
    ISSN (online) 1525-1438
    ISSN 1048-891X
    DOI 10.1097/IGC.0000000000001351
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