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Triple-Negative Breast Cancer Patient Subset Sees Benefit From Drug; Genomic Analysis Underway

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SAN ANTONIO – A subset of patients with early-stage triple-negative breast cancer may benefit from treatment with adjuvant capecitabine, according to a subgroup analysis of a Phase III study presented at the San Antonio Breast Cancer Symposium here this week, and researchers are applying genomic analysis to characterize them in more detail.

The overall study failed to show that treatment with adjuvant capecitabine was effective in early-stage triple-negative breast cancer patients. However, the subgroup analysis suggested potential benefit of the drug in patients with non-basal-like disease.

TNBC is a subtype of breast cancer that is usually treated with surgery and chemotherapy and is known to have a poor prognosis and higher rates of relapse compared to other subtypes that can be treated with targeted drugs. In the present study, led by Miguel Martin from the Complutense University of Madrid in Spain, more than 800 early-stage previously treated TNBC patients were randomized to receiving either the chemotherapy agent capecitabine or no drug.

After a median of seven years of follow up, 79.6 percent of patients receiving capecitabine didn't see their cancer return for five years, compared to 76.8 percent of patients in the observation arm, which is not a statistically significant finding. "The trial is formally negative," Martin said in a presentation at the meeting. "But when we looked at the subset analysis, we found very interesting information regarding the basal status of patients."

Researchers stratified TNBC patients according to whether they had a basal subtype, defined as having EGFR or CK5/6 expression by immunohistochemistry, or a non-basal subtype defined as lack of EGFR or CK5/6 expression. There was no difference in disease-free survival or overall survival in the basal-like group. However, in the non-basal-like subpopulation, five-year disease-free survival was 82.6 percent on capecitabine and 72.9 percent for those on observation and five-year overall survival was 89.5 percent and 79.6 percent, respectively.

Martin's group is following up on this finding, which may help explain why the study failed, even though the previously published CREATE-X trial showed that early-stage breast cancer patients, including those with TNBC, had prolonged disease-free survival and overall survival on capecitabine compared to controls. 

Experts at the meeting pointed out key differences between the Spanish trial and CREATE-X that could explain the different results. Joseph Sparano from Albert Einstein College of Medicine, for example, pointed out that in Martin's study, just 20 percent of patients on capecitabine had neoadjuvant treatment, and 25 percent of those patients (or 5 percent of the study population) had a pathologic complete response.

Patients who have a pathologic complete response after neoadjuvant treatment tend to have better outcomes than those that relapse. However, the study led by Martin was designed in 2004, when it was uncommon for TNBC patients to receive neoadjuvant treatment, so most patients in the trial received adjuvant rather than neoadjuvant treatment before receiving capecitabine.

In CREATE-X, by comparison, researchers evaluated capecitabine in early-stage breast cancer patients with residual disease after neoadjuvant treatment. Martin noted that patients in this study were at higher risk of relapse, which may account for the greater capecitabine efficacy seen in that study.

He continues to suspect that capecitabine is useful for some TNBC patients. "Our study is not finished because we are going to look at the genomic characteristics of this group defined as non-basal like," he said. " We want to know more about this group."

In the study, the researchers defined basal and non-basal subtypes using surrogate biomarkers with IHC. But Martin noted that basal-like breast cancers also have genomic characteristics and his group is using NanoString's Prosigna gene signature test to learn more about the molecular features of this group.

"We're in the era of personalized medicine," Martin said, but he bemoaned the fact that more often than not, TNBC patients are treated the same way, without considering disease subtypes. He noted the need for more biomarker-informed exploratory analysis of the kind his team is pursuing, though there is limited funding for studies involving older drugs.

Before capecitabine went generic a few years ago, it was a blockbuster drug for Genentech, marketed as Xeloda, and in 1998 was the first oral chemotherapy to be approved. "These types of trials [involving older drugs] are not interesting for pharma companies," Martin said.

On the other hand, pharma is recognizing opportunities to invest in precision oncology strategies that stand to have a positive impact on revenues. For example, other data presented at the meeting showed that Genentech’s Kadcyla is a potential treatment option for HER2-positive early breast cancer patients who still have evidence of cancer after neoadjuvant treatment with chemotherapy and a HER2-targeted drug before surgery. 

Kadcyla is an antibody-drug conjugate comprising one of Genentech’s flagship products, Herceptin (trastuzumab), and the covalently linked cytotoxic agent DM1. Experts at the meeting said the strong results from this study will help bolster greater use of Kadcyla in early breast cancer, which bodes well for Genentech, since the newer drug has a higher sticker price than Herceptin, which is slated to go off patent in June of 2019.

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