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Agendia Presents Data Supporting Predictive Claim For Breast Cancer Dx

This article has been updated from a prior version to include detatils on the price of Herceptin provided by a Genentech spokesperson.
At the San Antonio Breast Cancer Symposium last week, Agendia presented new clinical trial data for its MammaPrint breast cancer recurrence test that it claims supports expanding the assay’s indication to include predicting chemotherapy response.
This new data, which Agendia plans to submit along with other supportive clinical trials to the US Food and Drug Administration to update the test’s label, would put the Netherlands-based firm squarely in competition with Genomic Health.
While Genomic Health’s Oncotype DX is currently the only marketed test that gauges both breast cancer recurrence and chemotherapy benefit, the test has not been cleared by the FDA.
“The data that supports the predictive claim has been accumulated and it is being put together now in the form of an abstract which will be presented to the St. Gallen [Symposium] committee in Switzerland in March,” Richard Bender, Agendia’s Chief Medical Officer, told Pharmacogenomics Reporter this week. “A manuscript around that abstract is being developed right now and we’re hoping to present the manuscript and the supporting documents to the FDA in spring, and have our label indication extended to include a predictive claim sometime in 2009.”
According to Bender, MammaPrint’s new predictive indication will be similar to the indication for Oncotype DX’s. “Except our claims apply to both [estrogen receptor]+ and ER- patients, and our claim is supported by FDA clearance,” Bender added.
Cleared by the FDA in February 2007, MammaPrint costs $4,200. The price will not increase if the new indication is added, said Bender. By comparison, on July 1 Genomic Health increased the price of Oncotype DX by 4.5 percent to $3,820.
Agendia’s 70-gene panel was the first in vitro diagnostic multivariate index assay to be approved by the FDA. “We’ve been in competition with Oncotype DX since we entered the marketplace,” Bender said.
Oncotype DX is indicated to be used by women with early-stage, node-negative, ER+ invasive breast cancer who will be treated with hormone therapy. For its part, Genomic Health has been busy conducting studies to expand the indication of Oncotype DX into breast cancer patients who are node-positive and those treated with aromatase inhibitors.
In addition, the company, which also presented findings at the SABCS conference, is studying Oncotype DX in patients with other cancer types, including colon, prostate, lung, and ductal carcinoma in situ [see PGx Reporter 01-16-2008].
At the SABCS, Genomic Health presented data from studies looking at GRB7-dependent pathways as potential therapeutic targets in triple-negative breast cancer; quantitative gene-expression analysis using Oncotype DX in ductal carcinoma in situ that is adjacent to invasive ductal carcinoma; associations between estrogen receptor Alpha expression levels and ER genotypes; and risk of distant recurrence using Oncotype DX in postmenopausal primary breast cancer patients treated with anastrozole or tamoxifen in the TransATAC study.
At SABCS, Agendia separately announced data from another trial that suggested MammaPrint was able to correctly assess the status of HER-2+ patients traditionally ‘miscategorized’ as low risk for recurrence as high risk.
Predictive Claim
At SABCS, Laura van ‘t Veer, Agendia’s chief research officer, presented the data analyzing the association between pathological complete-response rate and the results of the MammaPrint test. 

“We’ve been in competition with Oncotype DX since we entered the marketplace.”

In the trial, a consecutive series of 167 patients who received neoadjuvant chemotherapy for stage II or III breast cancer were analyzed to assess MammaPrint’s potential predictive power. Approximately 20 percent of the 144 patients in the poor-prognosis signature group achieved a pathological complete response, whereas none of the patients with a good prognosis signature achieved a pathological complete response. After a median follow-up of 25 months, 19 relapses were seen in the poor-signature cohort and none in the good-signature group.
“These findings suggest tumors with a poor-prognosis MammaPrint signature are sensitive to chemotherapy,” Agendia said in a statement.
The company is planning to take to the FDA results from a multi-institutional 1,700-patient study supporting MammaPrint’s utility in gauging chemotherapy response. This study, the company hopes, will make the case of the predictive claim of its test. 
Bender said Agendia has been in discussions with key opinion leaders and insurers to educate them about MammaPrint, and the company is meeting with medical groups to get inclusion of MammaPrint in treatment guidelines.
Gauging HER-2
At SABCS, Michael Knauer from the Netherlands Cancer Institute presented findings from a study that suggested MammaPrint might be able to correctly identify a “substantial group of traditionally miscategorized low-risk HER2+ patients” as high risk for recurrence.
According to Knauer’s presentation, HER2+ patients are commonly identified as high risk for recurrence. But upon testing with MammaPrint, his team discovered that this subset of patients actually experienced a 10-year disease-free survival of close to 90 percent without treatment with Herceptin and adjuvant chemotherapy. 
“Additionally, in a subgroup of highly endocrine responsive HER2/NEU-positive patients, MammaPrint low risk patients had no relapse,” the researchers found. 
In the study of 169 HER2+ patients, MammaPrint classified 16 percent of patients as having a good-prognosis signature with a 10-year distant disease-free survival of 89 percent, compared to 84 percent of patients classified as having a poor prognosis signature with a distant disease-free survival of 64 percent.
This trial shows that “a substantial proportion, approximately 16 percent of HER-2-positive patients, actually follow a very positive course and could have chemotherapy with cytotoxic agents withheld,” Bender said.
HER2/NEU-overexpression is detected in between 15 percent and 20 percent of invasive breast cancers and considered to be a negative prognostic factor. Current treatment guidelines classify all HER2-positive breast cancer patients as being at high risk of relapse, and recommend treatment with Herceptin and chemotherapy.
Genentech's price to wholesalers for a 12-month course of Herceptin is approximately $41,544. This does not reflect the cost to patients and insurers, who may pay significantly more than the wholesale price. According to a Genentech spokesperson, if a person is underinsured or rendered uninsured through denial, then Genentech provides the medicine for free to the patient. 
Although the data is “quite compelling,” it needs to be independently validated, Bender noted. “If this could be supported in another set of patients … we could make a very significant pharmcoeconomic claim because you would be saving” the healthcare system money, and helping some patients avoid adverse reactions from unnecessary treatment with Herceptin and chemotherapy.
An independent validation study for this indication has already begun in Europe. According to Agendia, the results from this study will validated in the ongoing MINDACT (Microarray for Node-negative and 1-3 positive node Disease may Avoid ChemoTherapy) trial.
A spokesperson from Genentech told Pharmacogenomics Reporter this week that officials from the company were “intrigued” by Agendia’s presentation at SABCS.
“However, the numbers are quite small. Large series have looked at the prognosis of HER2-positive breast cancer, and determined this to be high risk disease,” the spokesperson said. “Only 169 patients were examined in this series, and the ‘low risk’ patients only constituted 16 percent of these. Drawing definitive conclusions from these small numbers is premature.”

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