scholarly journals Clinical and genomic insights into circulating tumor DNA-based alterations across the spectrum of metastatic hormone-sensitive and castrate-resistant prostate cancer

EBioMedicine ◽  
2020 ◽  
Vol 54 ◽  
pp. 102728 ◽  
Author(s):  
Manish Kohli ◽  
Winston Tan ◽  
Tiantian Zheng ◽  
Amy Wang ◽  
Carlos Montesinos ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Circulating Tumor Dna ◽  
Castrate Resistant Prostate Cancer ◽  
Hormone Sensitive ◽  
Castrate Resistant ◽  
Tumor Dna

Androgen receptor cfDNA longitudinal mutational analysis in metastatic castrate-resistant prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 197-197
Author(s):  
Elisa Marie Ledet ◽  
Patrick Cotogno ◽  
Whitley Hatton ◽  
Ellen Jaeger ◽  
Marcus W. Moses ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Mutational Analysis ◽  
Clinical Course ◽  
Circulating Tumor Dna ◽  
Driver Mutations ◽  
2Nd Generation ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Tumor Dna

197 Background: Androgen receptor (AR) mutations commonly occur in metastatic castrate resistant prostate cancer (mCRPC). Methods: Circulating tumor DNA (ctDNA) data were obtained from Guardant 360 assays throughout the clinical course of mCRPC patients (pts). Retrospective analysis for any pt with ≥ 3 Guardant assays at least 4 weeks apart were reviewed. Patients must have at least 1 AR mutation or amplification to qualify for inclusion. Statistical analyses, including chi-sq and longitudinal analyses, were conducted. Results: Of the 259 patients with Guardant testing, a total of 88 patients had at least 3 Guardant tests; of these, 59 (67%) had at least one AR alteration. Patients had a median of 4 Guardant assays (range 3-10). Patients with AR amplification, AR mutation or both were identified (23, 20, 16 respectively). The most common and clinically relevant AR mutations found alone or in combination with amplification were T878A (22%), L702H(19%), W742C (19%), and H875Y (10%). These particular functional AR mutations occurred alone in 16 patients. Only 3 patients had neither amplification nor common AR mutation. 17/59 patients were found to have at least one common AR mutation and amplification at some point (on same or different Guardant). One patient had seven different AR mutations with no amplification and two other patients had 3 AR mutations. Remainder of patients had either AR amplification or ≤ 2 alternative mutations. Patients with an AR amplification were 0.1138x (95% Cl 0.0289 - 0.4491) significantly less likely of having a common known functional mutation (p <0.002) at any point. Conclusions: Patients with the most frequently identified known functional AR mutations are less likely to have AR amplification in pts with mCRPC; these common AR mutations have been shown to be associated with resistance to 2nd generation androgen deprivation. Further clinical correlation between treatment regimen and %cfDNA of these and other non-AR driver mutations is planned.

Association of elevated serum CEA with visceral metastasis and distinctive circulating tumor DNA alterations in castrate-resistant prostate cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17023-e17023
Author(s):  
Alexander Bray ◽  
Pannaga G. Malalur ◽  
Leylah Drusbosky ◽  
Theodore Stewart Gourdin ◽  
Michael B. Lilly
Keyword(s):  
Prostate Cancer ◽  
Elevated Serum ◽  
Circulating Tumor Dna ◽  
Specific Gene ◽  
Non Invasive ◽  
Serum Carcinoembryonic Antigen ◽  
Castrate Resistant Prostate Cancer ◽  
Serum Cea ◽  
Castrate Resistant ◽  
Tumor Dna

e17023 Background: Serum carcinoembryonic antigen (CEA) is elevated in certain subtypes of castrate resistant prostate cancer (CRPC) such as aggressive variant prostate cancer (AVPC). Independent association of CEA expression with clinical stage and specific tumor gene variants could enable its use as a prognostic indicator and non-invasive biomarker of therapeutic response. Methods: Circulating tumor DNA (ctDNA) alterations in a commercially available panel of genes (Guardant Health) and serum CEA from 178 CRPC patients were retrospectively analyzed. These patients were defined as AVPC or non-AVPC based on the presence of 1 or more of the published Aparicio criteria (Aparicio et al, 2013). Clinical characteristics and ctDNA alterations were compared in patients with elevated and normal CEA. AVPC and non-AVPC patients were then compared to evaluate the uniqueness of CEA associated findings. Results: Patients with CRPC and elevated serum CEA were more likely to have liver (36.1% vs 12.0%, p = 0.002) and lung metastasis (19.4% vs 6.4%, p = 0.0441) compared to patients with normal CEA. When ctDNA profiles were analyzed there were no significant differences in rates of single nucleotide variants (SNVs) between patients with elevated and normal CEA. In contrast, patients with elevated CEA were significantly more likely to harbor copy number amplifications (CNAs) in BRAF, CDK6, FGR1, MET, CCNE1, MYC, KIT, CCND2, PIK3CA, RAF1, and KRAS. Of these, only PIK3CA and KRAS were significantly elevated in AVPC patients compared to non-AVPC patients. Relative to non-AVPC CRPC, patients with AVPC were significantly more likely to have clonal SNVs in TP53, PTEN, or RB (p = 0.0131). They were also more likely to have clonal SNVs in TP53 (p = 0.06). Conclusions: 1.) Elevated serum CEA is independently associated with visceral metastases in patients with CRPC. 2.) Elevated serum CEA in CRPC is associated with specific gene amplifications which are detectable by ctDNA analysis and not associated with AVPC as a whole. 3.) The ctDNA findings in patients with AVPC mirror previous tissue-based studies which documented recurrent genetic variations in TP53, PTEN, and RB (Aparicio et al, 2016). Together these findings outline a potential role for ctDNA profiling and serum CEA as non-invasive biomarkers in CRPC. They also suggest that elevated serum CEA may be associated with a genetically distinct subtype of AVPC.

PD52-12 ANALYSIS OF THE PROGNOSTIC SIGNIFICANCE OF CIRCULATING TUMOR DNA (CTDNA) IN METASTATIC CASTRATE RESISTANT PROSTATE CANCER (MCRPC)

2020 ◽  
Vol 203 ◽  
pp. e1094-e1095
Author(s):  
Justin Shaya* ◽  
J. Michael Randall ◽  
Frederick Millard ◽  
Razelle Kurzrock ◽  
J. Kellogg Parsons ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Prognostic Significance ◽  
Circulating Tumor Dna ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant ◽  
Tumor Dna

Why Chemotherapy Should be Given Early for Men with Metastatic Prostate Cancer

2015 ◽  
pp. e263-e269 ◽  
Author(s):  
Leonel F. Hernandez-Aya ◽  
Maha Hussain
Keyword(s):  
Prostate Cancer ◽  
De Novo ◽  
High Volume ◽  
High Response Rate ◽  
Phase Iii ◽  
Incurable Disease ◽  
Castration Resistant ◽  
Castrate Resistant Prostate Cancer ◽  
Hormone Sensitive ◽  
Castrate Resistant

Metastatic hormone-sensitive prostate cancer (mHSPC) is an incurable disease, and despite a high response rate to androgen-deprivation therapy (ADT), outcomes have not significantly changed for many decades. Earlier attempts at multitargeted strategies with the addition of cytotoxic chemotherapy to ADT did not affect survival. As more effective therapies are emerging, including cytotoxic therapy for patients with metastatic castrate-resistant prostate cancer (mCRPC), there is increasing interest for testing these drugs earlier in the disease course. The premise is that agents with clinical benefit in advanced mCRPC may have a better effect if used preemptively before the development of significant resistance and to attack earlier de novo androgen resistant/independent clones. The recent results of the phase III clinical trial E3805 investigating ADT with or without docetaxel in mHSPC provide compelling support for this strategy. Docetaxel combined with ADT significantly improved overall survival from 44 to 57.6 months (p = 0.0003), particularly in patients with high-volume disease (from 32.2 to 49.2 months; p = 0.0006). Longer follow-up is needed to assess the effect on patients with low disease burden. Further studies are needed to further maximize the antitumor effect in patients with mHSPC and to investigate the effects of advancing therapy to this disease setting on the efficacy of respective agents in the castration-resistant setting.

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