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St. Gallen Experts Recommend Oncotype DX for Chemoprediction; Support Breast Cancer Subtyping

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By Turna Ray

An international panel of breast cancer experts has recommended the use of Genomic Health's Oncotype DX as a predictive test to assess which breast cancer patients will benefit from chemotherapy.

Based on evidence presented at the St. Gallen International Breast Cancer Conference in March, a 51-member expert panel agreed that women with breast cancer should be treated with chemotherapy when gene array or immunohistochemistry testing shows their tumors display high histological grade, high cell proliferation measured by the presence of the Ki-67 protein, low hormone receptor status, positive HER2 status, or the molecular features of triple-negative breast cancer in invasive ductal carcinoma.

This week, members of the panel published highlights from the meeting in the Annals of Oncology and discussed their thinking on the best way to apply information on breast cancer subtypes to guide therapy. "A strong majority of the panel," around 85 percent "agreed that the 21-gene signature (Oncotype DX) may also be used where available to predict chemotherapy responsiveness in an endocrine responsive cohort where uncertainty remains after consideration of other tests, but the majority agreed that the chemopredictive properties of the 70-gene signature (MammaPrint) were not yet sufficiently established," Goldhirsch et al. wrote in the article.

Oncotype DX, marketed by Genomic Health since 2004, is a multi-gene expression test that gauges chemotherapy benefit in patients with estrogen receptor-positive, HER2-negative breast cancer. After analyzing the expression of multiple genes in a patient's tumor sample, the RT-PCR-based test yields a score that translates into high risk, low risk, or intermediate risk of breast cancer recurrence for patients.

The Oncotype DX recurrence score also corresponds to the likelihood that a woman will benefit from the addition of chemotherapy plus tamoxifen. The test is primarily used for disease prognosis and treatment benefit prediction in newly diagnosed, stage I or II, node-negative, estrogen receptor-positive breast cancer patients.

Oncotype DX is the only gene expression test recommended for patients with node-negative breast cancer that is estrogen-receptor positive or progesterone-receptor positive in treatment guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network.

According to a Genomic Health spokesperson, the St. Gallen panel reviewed existing data as well as physicians’ clinical experience to arrive at the latest recommendations. "For Oncotype DX this included more than 23 studies (validation and decision impact) and clinical experience in more than 200,000 patients worldwide," the spokesperson said via e-mail.

From the time of its launch in 2004 to March 31, 2011, more than 10,000 physicians in over 60 countries had ordered more than 200,000 Oncotype DX tests, according to the company. Since recording its first profitable year in 2010, Genomic Health has been focused on growing reimbursement of its leading products in international markets. A positive recommendation from an international expert panel, such as the St. Gallen authors, could further bolster Oncotype DX's acceptance in overseas markets.

In the first quarter of this year, Genomic Health's international product revenues increased to $4 million, or 8 percent of product revenue, compared with $1.9 million, or 4 percent of product revenue, in the first quarter of 2010 (PGx Reporter 05/04/2011).

According to Genomic Health, 11 studies in five countries including Spain, Germany, and the UK have demonstrated that when physicians used Oncotype DX to guide treatment recommendations, they changed their decision to prescribe chemotherapy more than 30 percent of the time, avoiding adverse reactions and costs associated with unnecessary treatment.

Meanwhile, around 70 percent of the panel voted against using Agendia's MammaPrint to gauge chemotherapy benefit. The US Food and Drug Administration in 2007 cleared MammaPrint as an in vitro diagnostic multivariate index assay that assesses whether a woman is at high or low-risk for breast cancer recurrence, despite ER status and any prior treatment.

Agendia promotes the chemopredictive aspects of its test score as well. Depending on whether the test yields a high or low risk of distant recurrence, a doctor can decide whether the patient should be treated with just tamoxifen, or needs chemotherapy in addition to hormonal therapy. Agendia did not respond to a request for comment on the St. Gallen panel's recommendation on MammaPrint.

The St. Gallen authors, led by Aron Goldhirsch of the European Institute of Oncology in Milan, Italy, noted that the chemopredictive features of both Oncotype DX and Mammaprint are being further studied in additional trials.

The National Cancer Institute is currently evaluating the effect of chemotherapy on women who fall in the "intermediate" recurrence score category after getting tested on Oncotype DX. The Trial Assigning Individualized Options for Treatment, or TAILORx, study is studying 10,000 patients from multiple sites in the US, Canada, Ireland, and Peru. The NCI-funded project finished enrolling patients last year, and is slated for completion in 2015.

The St. Gallen International Expert Consensus panel in 2009 recommended the use of multi-gene assays to guide treatment decisions in early breast cancer patients. However, experts found that intermediate scores from such multi-gene tests provide "little guidance in reaching a decision to use chemotherapy" (PGx Reporter 07/08/2009). The latest guidelines don't discuss Oncotype DX's intermediate score.

With regard to Agendia's test, MammaPrint is one of several molecular tests included in the US Food and Drug Administration and NCI-led I-SPY2 breast cancer trial, which is studying the use of such tests to guide treatment with investigational drugs.

The latest St. Gallen recommendations focus on how molecular subtyping may be used to guide breast cancer treatment strategies. "It is no longer tenable to consider breast cancer as a single disease. Subtypes can be defined by genetic array testing or approximations to this classification using immunohistochemistry," Goldhirsch et al. wrote. "These subtypes have different epidemiological risk factors, different natural histories, and different responses to systemic and local therapies."

The St. Gallen experts recommend that clinicians "should consider cases within the various distinct [breast cancer] subtypes in order to properly assess the relevant evidence and arrive at appropriate therapeutic advice."

There are a number of diagnostic firms that market subtyping tests. Agendia markets a test called BluePrint, which classifies breast cancer patients into basal-type, luminal-type, and ERBB2-type subclasses. This test is meant to provide additional insights into a woman's breast cancer following assessment of disease recurrence by MammaPrint.

In January, Arup Labs launched a multi-gene RT-PCR test, called PAM50, which measures 50 classifier genes and five control genes and categorizes patients into five intrinsic breast cancer subtypes that confer prognostic information: luminal A, luminal B, HER2-enriched, basal-like, and normal-like. NanoString is also developing a point-of-care subtyping test based on the PAM50 gene panel that will run on its nCounter multiplex gene expression platform (PGx Reporter 12/15/2010).

The St. Gallen expert panel "strongly agreed" that chemotherapy treatment in patients with luminal A subtype tumors was "less useful" due to lack of response. The panel also agreed that there is no preferred chemo regiment for patients with this tumor subtype. For patients with luminal B subtype tumors, the panel recommended a regimen containing anthracyclines and taxanes.

The majority of the panel favored a similar regimen for HER 2-positive patients, while for triple-negative breast cancer patients with ductal type disease they recommended a regimen with anthracyclines, taxanes, and an alkylating agent. In the latter subset, the panel recommended against the routine use of cisplatin or carboplatin.

"A slim majority agreed that dose-dense chemotherapy should be considered for [triple-negative breast cancer] patients, and the panel was strongly opposed to the inclusion of antiangiogenic therapies at this time," Goldhirsch et al. wrote. The researchers noted that trials are ongoing to see if anti-angiogenic treatments, such as Avastin, Erbitux, and Sutent, are efficacious in treating triple-negative breast cancer.


Have topics you'd like to see covered in Pharmacogenomics Reporter? Contact the editor at tray [at] genomeweb [.] com.

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