Circulating Cell-Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition.
TL;DR: Target and whole-exome sequencing of serial circulating cell-free DNA samples collected during a phase II trial of olaparib provide predictive, prognostic, response, and resistance data with "second hit" mutations first detectable at disease progression, suggesting clonal evolution from treatment-selective pressure and platinum resistance.
Abstract: Biomarkers for a more precise patient care are needed in metastatic prostate cancer (mPC). We have reported a Phase II trial (TOPARP-A) of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib in mPC, demonstrating antitumor activity associating with homologous recombination DNA repair defects. We now report targeted and whole exome sequencing of serial circulating-free DNA (cfDNA) samples collected during this trial. Decreases in cfDNA concentration independently associated with outcome in multivariable analyses (HR for overall survival at week 8: 0.19; 95%CI 0.06-0.56 p=0.003). All tumor tissue somatic DNA repair mutations were detectable in cfDNA; allele frequency of somatic mutations decreased selectively in responding patients (Chi-squared p<0.001). At disease progression, following response to olaparib, multiple sub-clonal aberrations reverting germline and somatic DNA repair mutations (BRCA2, PALB2) back in frame emerged as mechanisms of resistance. These data support the role of liquid biopsies as predictive, prognostic, response and resistance biomarker in mPC.
Citations
More filters
TL;DR: The authors review the progress made to date with PARP inhibitors, describe the expanding landscape of novel anticancer therapies targeting the DNA damage response and potential predictive biomarkers, mechanisms of resistance and combinatorial strategies are discussed.
Abstract: Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. These alterations promote the clonal evolution of cancer cells via the accumulation of driver aberrations, including gene copy-number changes, rearrangements and mutations; however, these same defects also create vulnerabilities that are relatively specific to cancer cells, which could potentially be exploited to increase the therapeutic index of anticancer treatments and thereby improve patient outcomes. The discovery that BRCA-mutant cancer cells are exquisitely sensitive to inhibition of poly(ADP-ribose) polymerase has ushered in a new era of research on biomarker-driven synthetic lethal treatment strategies for different cancers. The therapeutic landscape of antitumour agents targeting the DDR has rapidly expanded to include inhibitors of other key mediators of DNA repair and replication, such as ATM, ATR, CHK1 and CHK2, DNA-PK and WEE1. Efforts to optimize these therapies are ongoing across a range of cancers, involving the development of predictive biomarker assays of responsiveness (beyond BRCA mutations), assessment of the mechanisms underlying intrinsic and acquired resistance, and evaluation of rational, tolerable combinations with standard-of-care treatments (such as chemotherapeutics and radiation), novel molecularly targeted agents and immune-checkpoint inhibitors. In this Review, we discuss the current status of anticancer therapies targeting the DDR.
671 citations
The Royal Marsden NHS Foundation Trust1, Institute of Cancer Research2, University College London Hospitals NHS Foundation Trust3, Beatson West of Scotland Cancer Centre4, Clatterbridge Cancer Centre NHS Foundation Trust5, University of Leeds6, Queen's University Belfast7, Musgrove Park Hospital8, Blackburn College9, University of Southampton10, Royal Sussex County Hospital11, Western General Hospital12, Royal Lancaster Infirmary13, Cardiff University14
TL;DR: The TOPARP-B trial aims to prospectively validate the association between DDR gene aberrations and response to olaparib in metastatic castration-resistant prostate cancer by recruiting participants from 17 UK hospitals and following follow-up for a period of 24·8 months.
Abstract: Summary Background Metastatic castration-resistant prostate cancer is enriched in DNA damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively validate the association between DDR gene aberrations and response to olaparib in metastatic castration-resistant prostate cancer. Methods In this open-label, investigator-initiated, randomised phase 2 trial following a selection (or pick-the-winner) design, we recruited participants from 17 UK hospitals. Men aged 18 years or older with progressing metastatic castration-resistant prostate cancer previously treated with one or two taxane chemotherapy regimens and with an Eastern Cooperative Oncology Group performance status of 2 or less had tumour biopsies tested with targeted sequencing. Patients with DDR gene aberrations were randomly assigned (1:1) by a computer-generated minimisation method, with balancing for circulating tumour cell count at screening, to receive 400 mg or 300 mg olaparib twice daily, given continuously in 4-week cycles until disease progression or unacceptable toxicity. Neither participants nor investigators were masked to dose allocation. The primary endpoint of confirmed response was defined as a composite of all patients presenting with any of the following outcomes: radiological objective response (as assessed by Response Evaluation Criteria in Solid Tumors 1.1), a decrease in prostate-specific antigen (PSA) of 50% or more (PSA50) from baseline, or conversion of circulating tumour cell count (from ≥5 cells per 7·5 mL blood at baseline to ClinicalTrials.gov , NCT01682772 . Recruitment for the trial has completed and follow-up is ongoing. Findings 711 patients consented for targeted screening between April 1, 2015, and Aug 30, 2018. 161 patients had DDR gene aberrations, 98 of whom were randomly assigned and treated (49 patients for each olaparib dose), with 92 evaluable for the primary endpoint (46 patients for each olaparib dose). Median follow-up was 24·8 months (IQR 16·7–35·9). Confirmed composite response was achieved in 25 (54·3%; 95% CI 39·0–69·1) of 46 evaluable patients in the 400 mg cohort, and 18 (39·1%; 25·1–54·6) of 46 evaluable patients in the 300 mg cohort. Radiological response was achieved in eight (24·2%; 11·1–42·3) of 33 evaluable patients in the 400 mg cohort and six (16·2%; 6·2–32·0) of 37 in the 300 mg cohort; PSA50 response was achieved in 17 (37·0%; 23·2–52·5) of 46 and 13 (30·2%; 17·2–46·1) of 43; and circulating tumour cell count conversion was achieved in 15 (53·6%; 33·9–72·5) of 28 and 13 (48·1%; 28·7–68·1) of 27. The most common grade 3–4 adverse event in both cohorts was anaemia (15 [31%] of 49 patients in the 300 mg cohort and 18 [37%] of 49 in the 400 mg cohort). 19 serious adverse reactions were reported in 13 patients. One death possibly related to treatment (myocardial infarction) occurred after 11 days of treatment in the 300 mg cohort. Interpretation Olaparib has antitumour activity against metastatic castration-resistant prostate cancer with DDR gene aberrations, supporting the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice. Funding Cancer Research UK, AstraZeneca, Prostate Cancer UK, the Prostate Cancer Foundation, the Experimental Cancer Medicine Centres Network, and the National Institute for Health Research Biomedical Research Centres.
386 citations
TL;DR: Over the past 10 years, knowledge on the mechanism of action of PARP inhibitor as well as how tumours become resistant has been extended, and the opportunities for expanding the precision medicine approach with PARP inhibitors are discussed.
362 citations
TL;DR: Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance and suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice.
Abstract: Primary resistance to androgen receptor (AR)-directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naive mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers.Significance: Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice. Cancer Discov; 8(4); 444-57. ©2018 AACR.See related commentary by Jayaram et al., p. 392This article is highlighted in the In This Issue feature, p. 371.
345 citations
TL;DR: Recent advancements are explored and the current gaps in knowledge concerning each point of contact between cfDNA analysis and the different stages of cancer management are highlighted.
329 citations
References
More filters
TL;DR: The revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions, and a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included.
20,760 citations
TL;DR: Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP, and has antitumor activity in cancer associated with the BRCA1 or BRCa2 mutation.
Abstract: Background The inhibition of poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) is a potential synthetic lethal therapeutic strategy for the treatment of cancers with specific DNA-repair defects, including those arising in carriers of a BRCA1 or BRCA2 mutation. We conducted a clinical evaluation in humans of olaparib (AZD2281), a novel, potent, orally active PARP inhibitor. Methods This was a phase 1 trial that included the analysis of pharmacokinetic and pharmacodynamic characteristics of olaparib. Selection was aimed at having a study population enriched in carriers of a BRCA1 or BRCA2 mutation. Results We enrolled and treated 60 patients; 22 were carriers of a BRCA1 or BRCA2 mutation and 1 had a strong family history of BRCA-associated cancer but declined to undergo mutational testing. The olaparib dose and schedule were increased from 10 mg daily for 2 of every 3 weeks to 600 mg twice daily continuously. Reversible dose-limiting toxicity was seen in one of eight patients receiving 400 mg twice...
3,332 citations
University of Michigan1, Harvard University2, Massachusetts Institute of Technology3, Memorial Sloan Kettering Cancer Center4, University of Washington5, Institute of Cancer Research6, The Royal Marsden NHS Foundation Trust7, Cornell University8, Brigham and Women's Hospital9, Beth Israel Deaconess Medical Center10, University of Washington Medical Center11, University of Trento12, Wayne State University13, Johns Hopkins University14
TL;DR: This cohort study provides clinically actionable information that could impact treatment decisions for affected individuals and identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF.
2,713 citations
"Circulating Cell-Free DNA to Guide ..." refers background in this paper
...No 50% 28 28 23 18 15 15 9 (0) (5) (5) (2) (0) (6) (0) (4) (1) 9 5 (1) (2) (0) 2 0 0 4 >50% 18 No 50% 30 >50% 12 30 12 27 12 22 12 17 12 15 10 9 10 9 9 4 7 (0) (0) (3) (0) (5) (0) (4) (0) (2) (2) (6) (0) (0) (1) (5) (2) 3 6 (1) (1) 1 3 (2) (3) 0 1 (0) (2) (0) (0) 0 0 17 16 16 14 10 10 (1) (1) (0) (2) (4) (0) (1) (3) (1) 9 6 (3) (1) (0) 2 1 0 5 4 6 8 10 12 Months since trial entry 14 16 18 20 22 24 25 50...
[...]
...No 50% 28 25 8 4 4 3 2 (3) (16) (4) (0) (1) (1) (2) (0) (0) 1 1 (0) (0) (0) 0 0 0 1 >50% 18 No 50% 29 >50% 12 28 12 9 11 5 10 5 10 3 8 2 8 1 7 1 6 (1) (0) (18) (1) (4) (1) (0) (0) (2) (2) (1) (0) (2) (1) (0) (1) 1 5 (0) (1) 0 2 (0) (3) 0 1 (0) (1) (0) (0) 0 0 16 12 11 11 8 8 (2) (4) (1) (0) (3) (0) (1) (1) (1) 7 6 (3) (1) (0) 2 1 0 5...
[...]
...We previously reported that 20% to 30% of lethal prostate cancers have deleterious aberrations in genes involved in DNA repair by homologous recombination [homologous recombination deficiency (HRD)], including BRCA2, ATM, BRCA1, PALB2, FANCA, CHEK2, and CDK12 (4)....
[...]
TL;DR: In this article, the androgen-receptor splice variant 7 (AR-V7) was found to be associated with resistance to enzalutamide and abiraterone.
Abstract: Background The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone. Methods We used a quantitative reverse-transcriptase–polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression–free survival), clinical or radiographic progression–free survival, and overall survival. Resul...
2,221 citations
TL;DR: The mutational landscape of a heavily treated metastatic cancer is described, novel mechanisms of AR signalling deregulated in prostate cancer are identified, and candidates for future study are prioritize.
Abstract: Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains and losses, including ETS gene family fusions, PTEN loss and androgen receptor (AR) amplification, which drive prostate cancer development and progression to lethal, metastatic castration-resistant prostate cancer (CRPC). However, less is known about the role of mutations. Here we sequenced the exomes of 50 lethal, heavily pre-treated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment-naive, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPCs (2.00 per megabase) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1 that define a subtype of ETS gene family fusion-negative prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in approximately one-third of CRPCs (commonly through TMPRSS2:ERG fusions), is also deregulated through mutation. Furthermore, we identified recurrent mutations in multiple chromatin- and histone-modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with the AR, which is required for AR-mediated signalling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC), and showed that mutated FOXA1 represses androgen signalling and increases tumour growth. Proteins that physically interact with the AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX (also known as KDM6A) and ASXL1 were found to be mutated in CRPC. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signalling deregulated in prostate cancer, and prioritize candidates for future study.
2,141 citations
Additional excerpts
...No 50% 28 25 8 4 4 3 2 (3) (16) (4) (0) (1) (1) (2) (0) (0) 1 1 (0) (0) (0) 0 0 0 1 >50% 18 No 50% 29 >50% 12 28 12 9 11 5 10 5 10 3 8 2 8 1 7 1 6 (1) (0) (18) (1) (4) (1) (0) (0) (2) (2) (1) (0) (2) (1) (0) (1) 1 5 (0) (1) 0 2 (0) (3) 0 1 (0) (1) (0) (0) 0 0 16 12 11 11 8 8 (2) (4) (1) (0) (3) (0) (1) (1) (1) 7 6 (3) (1) (0) 2 1 0 5...
[...]