Why Nuclear Detection?

The Oncotype DX AR-V7 Nucleus Detect test is the first and only nuclear-localized assay to identify patients who will not respond to androgen receptor (AR)-targeted therapy (like abiraterone (Zytiga®), enzalutamide (Xtandi®) and apalutamide (Erleada®) and should receive chemotherapy or other therapies instead.2-5 By identifying AR-V7 protein in the nucleus of circulating tumor cells (CTCs), the AR-V7 Nucleus Detect test eliminates false positives and detects resistance to AR-targeted therapies with unparalleled specificity.4

How AR-V7 causes resistance to AR-targeted therapies

Tumors can adapt (and become resistant) to AR-targeted treatments. One of the most common adaptations is AR-V7—a protein variant of the androgen receptor. This splice variant is constitutively active and it lacks the ligand binding domain, which is critical for the effectiveness of AR-targeted therapies. Patients with nuclear AR-V7 protein receive no benefit from AR-targeted therapies, but may still respond to taxane chemotherapy.1-6

AR-V7 is a splice variant of the androgen receptor (AR) that lacks the ligand binding domain2
Ligand Image
AR-V7-positive patients' tumors are resistant to abiraterone and enzalutamide1,3,4

The percentage of patients with AR-V7 in the nucleus (nuclear AR-V7+ patients) increases with exposure to multiple therapies including AR-targeted therapies2:

  • Roughly 1 in 5 patients (18%) are nuclear AR-V7+ after receiving one round of therapy.
  • Roughly 1 in 3 patients (31%) are nuclear AR-V7+ after receiving two rounds of therapy.

Why nuclear localization eliminates false positives

The AR-V7 Nucleus Detect test detects protein in the nucleus of circulating tumor cells (not cytoplasmic AR-V7)—making it more specific than assays that do not localize AR-V7 identification.

Studies show that AR-V7 protein found in the nucleus of CTCs is an absolute indicator of resistance. Although AR-V7 proteins are also found in the cytoplasm, transcription of tumor growth genes occurs in the nucleus.3 In addition, some AR-V7 protein does not translocate to the nucleus; and some mRNA does not translate into protein.3 As a result, nuclear localization of the AR-V7 protein is important to avoid the potential for false positives.

  • 1 Cytoplasmic AR-V7 translocates into the nucleus
  • 2 Nuclear AR-V7 binds to DNA
  • 3 Transcription of tumor growth genes
  • 4 Translation of tumor-growth gene mRNA into protein

Nuclear Activity Image

REFERENCES

1. Antonarakis et al. N Engl J Med. 2014.
2. Scher et al. JAMA Oncol. 2016.
3. Scher et al. Eur Urol. 2016.
4. Antonarakis et al. JAMA Oncol. 2015.
5. Scher et al. JAMA Oncol. 2018.

 

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