AR Findings Highlight Detailed Tumor-Profiling Study

March 7, 2014

Article

Joyce A. O’Shaughnessy, MD

A wide-ranging analysis of more than 5500 breast cancer tumors that combined genomic and protein expression testing has identified promising targets to explore for treating patients with poor prognoses, with particularly notable findings involving androgen receptor (AR) expression,¹according to Joyce A. O’Shaughnessy, MD. Nearly 36% of the samples were from patients with triple-negative breast cancer (TNBC), making the study the largest genomic analysis in that disease setting to date.

The clues yielded through the analysis confirm the utility of multiplatform molecular profiling in identifying targets that could help oncologists direct patients who have metastatic disease, or who are not responding to standard therapies, into clinical trials, said O’Shaughnessy. In some instances, drugs aimed at these targets already have been approved.

O’Shaughnessy, who is chair of Breast Cancer Research at Baylor Charles A. Sammons Cancer Center, Texas Oncology and US Oncology, presented findings from the analysis at the 2013 San Antonio Breast Cancer Symposium (SABCS).¹

She discussed her research in an interview in advance of MBCC, where she is serving as a faculty member. O’Shaughnessy’s expertise includes using emerging technologies to explore novel therapies, particularly for TNBC. Her presentation during Thursday’s mini-symposium was entitled “Human Subject Implications of Genomic Profiling of Tumors.”

The clinical utility of next-generation sequencing for managing patients with high-risk or metastatic breast cancer continues to progress with the development of gene expression assays, and genomic profiling of newly diagnosed patients in these settings “will increasingly allow for early intervention with rational targeted therapies that could very significantly improve patients’ outcomes,” O’Shaughnessy said in her MBCC presentation.

Study Generates Trove of Data

In the study that she led, O’Shaughnessy and colleagues used a multifaceted tool developed by Caris Life Sciences, a Texas-based company. The Caris Molecular Intelligence platform examines tumors for gene mutations, protein expression, and/or gene amplification using next-generation sequencing technologies, immunohistochemistry (IHC), and in situ hybridization testing. Some 15 protein markers and 17 gene mutations were explored in the study, including the potential correlations and trends among the values.

The 5521 samples evaluated in the study were collected from 2009 to 2013.

“About half of them were primary breast cancer tissues and half of them were metastatic breast cancer tissues, and they were obtained from patients who had a poor outcome,” said O’Shaughnessy.

Overall, 52.8% of the samples were either estrogen receptor (ER)- or progesterone receptor (PR)-positive and HER2-negative. One of the study’s primary goals was to distinguish molecular differences between TNBC and other breast cancers, and a total of 35.8% of the samples turned out to be TNBC.

AR Findings Compelling

Several of the study’s most striking findings came from the information yielded through the analyses of AR expression. “The androgen receptor story is emerging as a potentially very important one in ER-negative breast cancer in general, be it triple-negative or ER-negative/ HER2-positive,” said O’Shaughnessy. She said the patient populations in the study were large enough to generate data that could guide drug development efforts. Key AR findings include:

AR expression was measured in 50% of the ER-negative/ HER2-positive samples and 18% of TNBC cases, suggesting it is prevalent enough to serve as a therapeutic target. (IHC positivity threshold of O+, <10%, or ≥/+ and ≥ 10%)
Nearly all of the AR-positive samples displayed evidence of aberrations in the PI3K pathway through PIK3CA mutations, or PTEN mutations, or loss of expression.
Decreased proliferation as measured by Ki67 is associated with AR expression in TNBC but not ER-positive or HER2-positive disease.

O’Shaughnessy said the proliferation analysis has clinical implications.

“About half of the triple-negative patients who have AR positivity have a low Ki67, a low cell division rate under 30%, and that is low for triple-negative,” she said. “There are a number of clinical trials going on right now in triple-negative breast cancer patients looking for those who have androgen receptor positivity, and in terms of finding them in the clinic we want to be alert that if they have a slower-growing cancer or Ki67 under 30% they are probably enriched for the androgen receptor.”

However, more highly proliferative TNBCs can also be AR-positive, noted O’Shaughnessy.

Using AR-Targeting Agents Now

O’Shaughnessy believes that the evidence is strong enough now for clinicians to consider whether AR-targeting agents currently approved for patients with prostate cancer may be appropriate for patients with metastatic breast cancer. She is participating in a phase II study of enzalutamide (Xtandi) in patients with advanced AR-positive TNBC.²The primary outcome of the single-arm, open-label study will be the clinical benefit rate, defined as a combination of the best complete responses, partial responses, or stable disease ≥16 weeks.

Bicalutamide, initially approved to treat men with metastatic prostate cancer in 1995, has demonstrated promising results in a study led by Memorial Sloan Kettering Cancer Center, O’Shaughnessy noted. The study screened 424 patients with ER- and PR-negative breast cancer and went on to treat the 12% who also were AR positive.³Gucalp et al reported a 6-month clinical benefit rate of 19% (95% CI, 7%-39%) among patients with AR-positive metastatic breast cancer who received 150 mg bicalutamide daily, with no grade 4/5 treatment-related adverse events. Researchers said the results constitute a “proof of principle” for the use of androgen blockade in this patient population.

The data indicate that “Bicalutamide is reasonable for any oncologist to consider in a metastatic triple-negative, AR-positive patient who needs a therapeutic option,” said O’Shaughnessy. “I think that is actionable.”

Table. A Snapshot of AR Positivity: % of AR-positive patients in 3 largest subgroups in study

AR indicates androgen receptor; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor. O’Shaughnessy JA et al. 2013 San Antonio Breast Cancer Symposium. Abstract PD4-1.

References

O’Shaughnessy JA, Gatalica Z, Kimbrough JM, Millis SZ. Comparison of mutations and protein expression in potentially actionable targets in 5500 triple negative vs non-triple negative breast cancers. Presented at: 2013 San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, TX. Abstract PD4-1.
Traina TA, O’Shaughnessy J, Kelly C, et al. A phase 2 single-arm study of the clinical activity and safety of enzalutamide in patients with advanced androgen receptor-positive triple-negative breast cancer. Presented at: 2013 San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, TX. Abstract OT3-2-08.
Gucalp A, Tolaney S, Isakoff SJ, et al. Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer [published online August 21, 2013]. Clin Cancer Res. 2013;19(19):5505-5512.

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