Bone biopsy protocol for advanced prostate cancer in the era of precision medicine

Sailer, Verena; Schiffman, Marc; Kossaï, Myriam; Cyrta, Joanna; Beg, Shaham; Sullivan, Brian; Pua, Bradley B.; Lee, Kyungmouk Steve; Talenfeld, Adam D.; Nanus, David M.; Tagawa, Scott T.; Robinson, Brian D.; Rao, Rema; Pauli, Chantal; Bareja, Rohan; Beltrán, Luis; Sigaras, Alexandros; Eng, Kenneth; Elemento, Olivier; Sboner, Andrea; Rubin, Mark A.; Beltran, Himisha; Mosquera, Juan Miguel

doi:10.1002/cncr.31173

Cited by 45 publications

(51 citation statements)

References 30 publications

(77 reference statements)

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“…However, there are some limitations: we show that CTC counts correlate with ctDNA fraction (Supplementary figure 1), and patients with low ctDNA fraction starting first-and second line mCRPC therapy, with few exceptions, have low CTC counts (Supplementary figure 9); previous work demonstrate poor success rate (~10 %) in obtaining high-quality CTC sequencing data from isolated cells [61,62] necessitating multiple 10 ml blood tubes for CTC analysis in first-and second line patients. However, recent improvements in harvesting metastatic tissue [29] may provide a fall-back if ctDNA profiling fail to identify any relevant biomarkers. As the success-rate of harvesting high-quality metastatic tissue is also correlated to tumor burden [26,27], prospective validation is needed to establish the most feasible approach.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple studies on the acquisition of tumor tissue with or without direct image-guidance report a range of success rates [25][26][27][28]. A recent effort, focusing on methodological improvements, obtained >20% cell content in the majority of bone biopsies [29]. Circulating tumor DNA is a viable alternative to metastatic tissue with demonstrated high fractions of ctDNA [30][31][32][33] enabling sensitive detection of somatic variation and direct comparisons to metastatic tissue reveal high concordance [30,34,35].…”

Section: Introductionmentioning

confidence: 99%

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Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

Mayrhofer

Laere

Whitington

et al. 2018

Preprint

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Background: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. Methods:A combination of targeted-and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients.Results: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first line mCRPC therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%).Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥0.1 ctDNA fraction). Sequencing of non-repetitive intronic-and exonic regions of PTEN, RB1and TP53 detected biallelic inactivation in 47.5%, 20.3% and 44.1% of samples with ≥0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays.Conclusions: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenge the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

Mayrhofer

Laere

Whitington

et al. 2018

Preprint

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“…Multiple studies on the acquisition of tumor tissue with or without direct image guidance report a range of success rates [ 28 – 31 ]. A recent effort, focusing on methodological improvements, obtained > 20% cell content in the majority of bone biopsies [ 32 ]. Circulating tumor DNA is a viable alternative to metastatic tissue with demonstrated high fractions of ctDNA [ 33 – 36 ] enabling sensitive detection of somatic variation, and direct comparisons to metastatic tissue have revealed high concordance [ 33 , 37 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

et al. 2018

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BackgroundThere are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited.MethodsA combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients.ResultsctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥ 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with ≥ 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays.ConclusionsctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.Electronic supplementary materialThe online version of this article (10.1186/s13073-018-0595-5) contains supplementary material, which is available to authorized users.

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“…Unguided iliac crest bone marrow biopsies of metastases seen on CT were positive for PCa in 62.5% of the cases, and in only 45% sufficient tumor cells were obtained for molecular analysis [11]. Molecular analysis success rates after CT-guided biopsies from bone tissue were similar, ranging from 33 to 44% of all biopsies [12][13][14]. This can be compared to the previous performance of our own institute, by looking at the success rate of 103 patients with prostate cancer that we included in the CPCT-02 study, a nationwide study investigating the genomic landscape in relation to response to systemic anticancer therapy using WGS [10].…”

Section: Discussionmentioning

confidence: 96%

68Ga-PSMA-PET/CT and Diffusion MRI Targeting for Cone-Beam CT-Guided Bone Biopsies of Castration-Resistant Prostate Cancer Patients

Steenbergen¹,

Smits

Scheenen³

et al. 2019

Cardiovasc Intervent Radiol

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Introduction Precision medicine expands the treatment options for metastatic castration-resistant prostate cancer (mCRPC) by targeting druggable genetic aberrations. Aberrations can be identified following molecular analysis of metastatic tissue. Bone metastases, commonly present in mCRPC, hinder precision medicine due to a high proportion of biopsies with insufficient tumor cells for nextgeneration DNA sequencing. We aimed to investigate the feasibility of incorporating advanced target planning and needle guidance in bone biopsies and whether this procedure increases biopsy tumor yield and success rate of molecular analysis as compared to the current standards, utilizing only CT guidance. Materials and Methods In a pilot study, ten mCRPC patients received 68 Ga-prostate-specific membrane antigen (PSMA)-PET/CT and diffusion-weighted MRI as biopsy planning images. These datasets were fused for targeting metastatic lesions with high tumor densities. Biopsies were performed under cone-beam CT (CBCT) guidance. Feasibility of target planning and needle guidance was assessed, and success of molecular analysis and tumor yield were reported. Results Fusion target planning and CBCT needle guidance were feasible. Nine out of ten biopsies contained prostate cancer cells, with a median of 39% and 40% tumor cells by two different sequencing techniques. Molecular analysis was successful in eight of ten patients (80%). This exceeds previous reports on CT-guided biopsies that ranged from 33 to 44%. In two patients, important druggable aberrations were found. Discussion A biopsy procedure using advanced target planning and needle guidance is feasible and can increase the success rate of molecular analysis in bone metastases, thereby having the potential of improving treatment outcome for patients with mCRPC. Level of Evidence Level 4, case series.

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Bone biopsy protocol for advanced prostate cancer in the era of precision medicine

Abstract: This prostate cancer bone biopsy protocol ensures a valuable source for high-quality DNA and RNA for tumor sequencing and may be used to detect actionable alterations and resistance mechanisms in patients with bone metastases. Cancer 2018;124:1008-15. © 2017 American Cancer Society.

Cited by 45 publications

References 30 publications

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis

68Ga-PSMA-PET/CT and Diffusion MRI Targeting for Cone-Beam CT-Guided Bone Biopsies of Castration-Resistant Prostate Cancer Patients

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