Clinical and Genomic Characterization of Low–Prostate-specific Antigen, High-grade Prostate Cancer,European Urology

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Clinical and Genomic Characterization of Low–Prostate-specific Antigen, High-grade Prostate Cancer
European Urology ( IF 25.3 ) Pub Date : 2018-02-22 , DOI: 10.1016/j.eururo.2018.01.043
Brandon A Mahal ₁ , David D Yang ₂ , Natalie Q Wang ₃ , Mohammed Alshalalfa ₃ , Elai Davicioni ₃ , Voleak Choeurng ₃ , Edward M Schaeffer ₄ , Ashley E Ross ₅ , Daniel E Spratt ₆ , Robert B Den ₇ , Neil E Martin ₈ , Kent W Mouw ₈ , Peter F Orio ₈ , Toni K Choueiri ₉ , Mary-Ellen Taplin ₉ , Quoc-Dien Trinh ₁₀ , Felix Y Feng ₁₁ , Paul L Nguyen ₈

Affiliation

Harvard Radiation Oncology Program, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
GenomeDx Biosciences, Vancouver, British Columbia, Canada.
Department of Urology, Northwestern University, Chicago, IL, USA.
James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA.
Harvard Medical School, Boston, MA, USA; Department of Radiation Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA; Department of Medical Oncology, Brigham and Women's Hospital/Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA; Division of Urological Surgery, Brigham and Women's Hospital, Boston, MA, USA.
Departments of Radiation Oncology, Urology, and Medicine and Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA, USA.

Background

The consequences of low prostate-specific antigen (PSA) in high-grade (Gleason 8–10) prostate cancer are unknown.

Objective

To evaluate the clinical implications and genomic features of low-PSA, high-grade disease.

Design, setting, and participants

This was a retrospective study of clinical data for 494 793 patients from the National Cancer Data Base and 136 113 patients from the Surveillance, Epidemiology, and End Results program with cT1–4N0M0 prostate cancer (median follow-up 48.9 and 25.0 mo, respectively), and genomic data for 4960 patients from the Decipher Genomic Resource Information Database. Data were collected for 2004–2017.

Outcome measurements and statistical analysis

Multivariable Fine-Gray and Cox regressions were used to analyze prostate cancer–specific mortality (PCSM) and all-cause mortality, respectively.

Results and limitations

For Gleason 8–10 disease, using PSA 4.1–10.0 ng/ml (n = 38 719) as referent, the distribution of PCSM by PSA was U-shaped, with an adjusted hazard ratio (AHR) of 2.70 for PSA ≤2.5 ng/ml (n = 3862, p < 0.001) versus 1.97, 1.36, and 2.56 for PSA of 2.6–4.0 (n = 4199), 10.1–20.0 (n = 17 372), and >20.0 ng/ml (n = 16 114), respectively. By contrast, the distribution of PCSM by PSA was linear for Gleason ≤7 (using PSA 4.1–10.0 ng/ml as the referent, n = 359 898), with an AHR of 0.41 (p = 0.13) for PSA ≤2.5 ng/ml (n = 37 812) versus 1.38, 2.28, and 4.61 for PSA of 2.6–4.0 (n = 54 152), 10.1–20.0 (n = 63 319), and >20.0 ng/ml (n = 35 459), respectively (p_interaction < 0.001). Gleason 8–10, PSA ≤2.5 ng/ml disease had a significantly higher PCSM than standard high-risk/very high-risk disease with PSA >2.5 ng/ml (AHR 2.15, p = 0.002; 47-mo PCSM 14% vs 4.9%). Among Gleason 8–10 patients treated with radiotherapy, androgen deprivation therapy was associated with a survival benefit for PSA >2.5 ng/ml (AHR 0.87; p < 0.001) but not ≤2.5 ng/ml (AHR 1.36; p = 0.084; p_interaction = 0.021). For Gleason 8–10 tumors, PSA ≤2.5 ng/ml was associated with higher expression of neuroendocrine/small-cell markers compared to >2.5 ng/ml (p = 0.046), with no such relationship for Gleason ≤7 disease.

Conclusions

Low-PSA, high-grade prostate cancer has very high risk for PCSM, potentially responds poorly to androgen deprivation therapy, and is associated with neuroendocrine genomic features.

Patient summary

In this study, we found that low–prostate-specific antigen, high-grade prostate cancer has a very high risk for prostate cancer death, may not respond well to androgen deprivation therapy, and is associated with neuroendocrine genomic features. These findings suggest that current nomograms and treatment paradigms may need modification.

中文翻译：

低前列腺特异性抗原、高级别前列腺癌的临床和基因组特征

背景

高级别（格里森 8-10）前列腺癌中低前列腺特异性抗原 (PSA) 的后果尚不清楚。

客观的

评估低PSA、高级别疾病的临床意义和基因组特征。

设计、设置和参与者

这是一项对来自国家癌症数据库的 494 793 名患者和来自监测、流行病学和最终结果计划的 cT1–4N0M0 前列腺癌患者的临床数据的回顾性研究（中位随访时间分别为 48.9 和 25.0 个月），以及来自解密基因组资源信息数据库的 4960 名患者的基因组数据。收集了 2004-2017 年的数据。

结果测量和统计分析

多变量 Fine-Gray 和 Cox 回归分别用于分析前列腺癌特异性死亡率 (PCSM) 和全因死亡率。

结果和限制

对于 Gleason 8-10 疾病，使用 PSA 4.1-10.0 ng/ml ( n = 38 719) 作为参考，PSA 的 PCSM 分布呈 U 形，PSA ≤2.5 ng 的调整后风险比 (AHR) 为 2.70 /ml ( n = 3862, p < 0.001) 对比 1.97、1.36 和 2.56，PSA 为 2.6–4.0 ( n = 4199)、10.1–20.0 ( n = 17 372) 和 >20.0 ng/ml ( n = 173 ) 114），分别。相比之下，对于 Gleason ≤7（使用 PSA 4.1-10.0 ng/ml 作为参考，n = 359 898），PSA 对 PCSM 的分布是线性的，PSA ≤2.5 ng/ml的 AHR 为 0.41 ( p = 0.13) ml ( n = 37 812) 对比 1.38、2.28 和 4.61，PSA 为 2.6–4.0 ( n = 54 152)、10.1–20.0 ( n = 63 319) 和 >20.0 ng/ml ( n = 35 459)（p_相互作用 < 0.001）。格里森 8-10，PSA ≤ 2.5 ng/ml 疾病的 PCSM 显着高于 PSA > 2.5 ng/ml 的标准高风险/非常高风险疾病（AHR 2.15，p = 0.002；47-mo PCSM 14% vs 4.9%）。在接受放射治疗的格里森 8-10 名患者中，雄激素剥夺疗法与 PSA >2.5 ng/ml（AHR 0.87；p < 0.001）但不≤2.5 ng/ml（AHR 1.36；p = 0.084；p）的生存获益相关_相互作用 = 0.021）。对于 Gleason 8-10 肿瘤，PSA ≤2.5 ng/ml 与神经内分泌/小细胞标志物的更高表达相关，而大于 2.5 ng/ml ( p = 0.046)，而对于 Gleason ≤7 疾病则没有这种关系。