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Resistance to Androgen-Pathway Drugs in Prostate Cancer To the Editor: Antonarakis and colleagues (Sept. 11 issue)1 reported a significant association between the presence of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells and shorter prostate-specific antigen (PSA) progression–free survival, clinical or radiographic progression–free survival, and overall survival in men with metastatic castration-resistant prostate cancer who were treated with enzalutamide or abiraterone. Several treatment options (abiraterone, enzalutamide, sipuleucel-T, and radium-223) have recently been shown to prolong survival in men with metastatic castration-resistant prostate cancer who have not previously been treated with chemotherapy; the identification of reliable biomarkers that can predict response should optimize treatment with these approaches. A study by Loriot and colleagues2 suggests that the duration of sensitivity to previous androgen-deprivation therapy (ADT) is predictive of the efficacy of subsequent endocrine manipulations in patients with castrationresistant prostate cancer. Loriot et al. found that 58% of patients with a duration of sensitivity to previous therapy of at least 16 months had a PSA response to subsequent treatment, as compared with 18% of patients with a duration of sensitivity of less than 16 months (P = 0.01). Antonarakis et al. observed no PSA response to abiraterone or enzalutamide in men who tested positive for AR-V7. We wonder about the relationship between AR-V7 positivity and the duration of response to previous ADT. Mehmet A.N. Şendur, M.D. Muhammed B. Akıncı, M.D. Bülent Yalçın, M.D.
1. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance
to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014;371:1028-38. 2. Loriot Y, Massard C, Albiges L, et al. Personalizing treatment in patients with castrate-resistant prostate cancer: a study of predictive factors for secondary endocrine therapies activity. J Clin Oncol 2012;30:Suppl:213. abstract. DOI: 10.1056/NEJMc1412594
To the Editor: Antonarakis et al. reported that the detection of AR-V7 in circulating tumor cells was predictive of resistance to enzalutamide and abiraterone. Some patients with undetectable AR-V7 at baseline subsequently converted to AR-V7–positive status during the course of treatment, suggesting that perhaps AR-V7 could serve as a dynamic biomarker to detect acquired resistance. What were the durations of response and the clinical courses of the men after they tested positive for AR-V7? Yukinori Ozaki, M.D. Yuji Miura, M.D. Toshimi Takano, M.D. Toranomon Hospital Tokyo, Japan
[email protected]
this week’s letters 2233 Resistance to Androgen-Pathway Drugs in Prostate Cancer 2235 Ph-like Acute Lymphoblastic Leukemia in Adults 2236 Ectopic Fat in Insulin Resistance, Dyslipidemia, and Cardiometabolic Disease 2238 A Man with a Rash, Headache, Fever, Nausea, and Photophobia
Yıldırım Beyazıt University Ankara, Turkey
[email protected] No potential conflict of interest relevant to this letter was reported.
2239 Oral Arsenic and Retinoic Acid for Non–HighRisk Acute Promyelocytic Leukemia
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No potential conflict of interest relevant to this letter was reported. DOI: 10.1056/NEJMc1412594
To the Editor: Antonarakis et al. did not determine whether point mutations existed in the androgen-receptor gene (AR) in circulating tumor cells of men with castration-resistant prostate cancer. Using immunomagnetic bead-based isolation of circulating tumor cells (ProstateCancer Select, AdnaGen) followed by a quantitative realtime reverse-transcriptase–polymerase-chainreaction assay and subsequent pyrosequencing across regions of AR known to harbor hot-spot mutations,1 we prospectively examined circulating tumor cells from 45 patients with histologically confirmed, castration-resistant prostate cancer who were undergoing ADT. We detected circulating tumor cells in 38 of 45 patients and the presence of AR-V7 in 17 of these 38 patients (45%). In addition, we detected one activating point mutation (p.T877A) in AR in an AR-V7–negative patient. We did not detect a p.F876L AR point mutation (which confers resistance to enzalutamide). These results suggest that AR-V7 is more commonly associated with resistance to ADT than are mutations in AR and that AR-V7 and resistance-conferring mutations in AR rarely coexist in the same tumor. Julie Steinestel, M.D. Andres J. Schrader, M.D. University Hospital Muenster Muenster, Germany
[email protected]
Manuel Luedeke, Ph.D. Ulm University Ulm, Germany No potential conflict of interest relevant to this letter was reported.
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AR-V7–negative patients. In the 18 AR-V7–positive men, the median duration of response to primary ADT was 17 months (range, 1 to 78); in the 44 AR-V7–negative men, the median duration of response to primary ADT was also 17 months (range, 2 to 120). Therefore, it is unlikely that the detection of AR-V7 could be predicted simply on the basis of a short duration of response to firstline ADT. In response to the comment by Ozaki and colleagues: only six patients in our study converted from AR-V7–negative status at baseline to AR-V7–positive status during the course of therapy with enzalutamide and abiraterone. All these patients had clinical or radiographic progression of their disease within 3 months after becoming AR-V7–positive. We speculate that these patients may have had AR-V7 in their circulating tumor cells even in their baseline blood samples but that the level of AR-V7 was below the lower limit of detection of the assay. We congratulate Steinestel and colleagues for prospectively examining circulating tumor cells from 38 patients with castration-resistant prostate cancer for the presence of AR-V7 as well as AR point mutations. Although we agree that AR-V7 does not usually coexist with AR point mutations, our group has recently identified a patient with both AR-V7 and the L701H AR mutation (which renders the androgen receptor susceptible to activation by glucocorticoids).2,3 Ongoing studies involving RNA sequencing will better define the prevalence of coexisting androgen-receptor splice variants and AR genomic alterations. Emmanuel S. Antonarakis, M.D. Mary Nakazawa, M.H.S. Jun Luo, Ph.D.
1. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants
Johns Hopkins University Baltimore, MD
[email protected]
DOI: 10.1056/NEJMc1412594
Since publication of their article, the authors report no further potential conflict of interest.
of resistance to antiandrogen therapy. Nat Med 2004;10:33-9.
1. Loriot Y, Massard C, Albiges L, et al. Personalizing treat-
The authors reply: Şendur and colleagues correctly point out that a previous study suggests an association between the duration of response to first-line ADT and subsequent responses to additional endocrine manipulations in men with castration-resistant prostate cancer.1 We did not observe a difference in the duration of response to primary ADT between the AR-V7–positive and
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ment in patients with castrate-resistant prostate cancer: a study of predictive factors for secondary endocrine therapies activity. J Clin Oncol 2012;30:Suppl:213. abstract. 2. Nakazawa M, Lu C, Chen Y, Antonarakis E, Luo J. MP52-10 RNA sequencing of circulating tumor cells from men with castration-resistant prostate cancer. J Urol 2014;191(4):e583. 3. Zhao X-Y, Malloy PJ, Krishnan AV, et al. Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor. Nat Med 2000;6:703-6. DOI: 10.1056/NEJMc1412594
n engl j med 371;23 nejm.org december 4, 2014
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