H/I^SM

Identifying endocrine-resistant, ER+ patients

A common dilemma for oncologists is determining whether or not women diagnosed with estrogen receptor positive (ER+), lymph node negative breast cancer will benefit from endocrine therapy, particularly because nearly 22% of patients treated with tamoxifen will experience recurrence over 10-15 years.¹

Integration into clinical practice

Treatment options for breast cancer, including hormone therapy and/or chemotherapy, are chosen on the basis of endocrine responsiveness and prognostic risk factors.² Comprehending a patient’s potential to benefit from endocrine therapy or chemotherapy is vital to understanding overall risk of recurrence and best treatment options.

HOXB13:IL17BR Index

H/I measures the expression of HOXB13 and IL17BR. This index has been demonstrated to stratify breast cancer patients into high or low risk of recurrence, and preliminary data suggest that it may predict to benefit from endocrine therapy.^2-8

• HOXB13 and IL17BR assess the functionality of the estrogen signaling pathway in ER+ breast cancer
• Functional estrogen signaling (low H/I value) may predict the likelihood of benefit from endocrine therapy
• Dysfunctional estrogen signaling (high H/I value) may be predictive of a lack of benefit from endocrine therapy
• High H/I values in the presence of aggressive proliferation as measured by MGI (Molecular Grade Index) has been demonstrated to be predictive of a higher risk of distant recurrence in patients diagnosed with ER+ node-negative breast cancer.⁸

_{Patients with ER-positive, lymph node-negative breast cancer treated with endocrine therapy or combined chemoendocrine therapy (n = 93).}

Biology of HOXB13 and IL17BR

HOXB13 is a homeobox gene located on chromosome 17q21, an area harboring a number of genes involved in breast carcinogenesis, and:

• Is frequently over-expressed in breast cancer³
• Is negatively regulated by estrogen signaling in breast cancer cells⁸
• Promotes cell motility and invasive properties when over-expressed³
• Is oncogenic¹⁰
• Inhibits tamoxifen-induced apoptosis¹¹

IL17BR is a gene located at 3p21, a chromosomal region frequently lost in cancer, including breast cancer, and:

• Predicts functionality of estrogen-signaling pathway when high³
• Has immunoregulatory activity

Assay information

• Robust real-time RT-PCR assay
• Requires one adjacent H&E and two unstained slides from formalin-fixed paraffin embedded specimens
• Performed in a CAP accredited, CLIA-certified laboratory
• Results typically available within 3-5 working days of receipt of sample

Research collaborations

• Harvard Medical School / MGH, Boston, MA
• Mayo Clinic, Rochester, MN
• Baylor College of Medicine, Houston, TX
• Erasmus Medical Center, Netherlands
• Linköping University Hospital, Sweden

References:
1. Fisher B, et al. Treatment of lymph-node negative, estrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. Lancet. 2004; 364: 858-868.
2. Goldhirsch et al. Meeting highlights: International expert consensus on the primary therapy of early breast cancer. Ann Oncology 16: 1569-1583, 2005.
3. Ma, et al. A Two-Gene Expression Ratio Predicts Clinical Outcome in Breast Cancer Patients Treated with Tamoxifen Cancer Cell 5:607-16, 2004.
4. Goetz, et al. A Two-Gene Expression of Homeobox 13 and Interleukin-17B Receptor for Prediction of Recurrence and Survival in Women Receiving Adjuvant Tamoxifen Clinical Cancer Research 12(7):2080-87, 2006.
5. Ma, et al. The HOXB13:IL17BR Expression Index is a Prognostic Factor in Early-Stage Breast Cancer. Journal of Clinical Oncology, 24(28):4611-19, 2006.
6. Jansen, et al. Retrospective Study of the HOXB13-to-IL17BR Expression Ratio Related to Tumor Aggressiveness and Response to Tamoxifen in Recurrent Breast Cancer. Journal of Clinical Oncology, 25(6):662-668, 2007.
7. Jerevall, et al. Exploring the Two-Gene Ratio in Breast Cancer–Independent Roles for HOXB13 and IL17BR in Prediction of Clinical Outcome. Breast Cancer Research Treatment 102, April 2007.
8. Wang, et al. The Prognostic Biomarkers HOXB13, IL17BR and CHDH Are Regulated by Estrogen in Breast Cancer. Clinical Cancer Research 13(21): 6327-6334, November 1, 2007.
9. Ma, et al. A Five-Gene Molecular Grade Index and HOXB13:IL17BR Are Complementary Prognostic Factors in Early Stage Breast Cancer. Clinical Cancer Research 14(9): 2601-2608, May 1, 2008.
10. Miao, et al. HOXB13 Promotes Ovarian Cancer Progression. Proc Nat Acad Sci USA, 104:43, 17093-17098, 2006.
11. Sgroi, et al. Personal Communication, 2007.