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EORTC-NCI-AACR: Genomic Testing in Breast Cancer May Enhance Personalized Treatment: Update of I-SPY 2

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Key Points

  • MP1/2 status might be a useful adjunct in predicting which patients are likely to respond to which drugs or combinations.
  • BluePrint can identify a subset of patients with HR-positive, HER2-negative basal tumors who are more likely to respond to neoadjuvant chemotherapy.

New results from the long-running I-SPY 2 trial, which aimed to identify which new drugs or combinations of drugs are most effective in which types of breast cancer, demonstrated the usefulness of two genomic tests.

Laura van ‘t Veer, PhD, leader of the Breast Oncology Program at the University of California, San Francisco, told the 30th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, “Effective breast cancer treatment depends on recognizing the biology of the tumor. MammaPrint and BluePrint are two tests that recognize disease at risk of early recurrence and the different molecular subtypes.”

I-SPY 2 is a phase II randomized clinical trial testing several treatments, alone or in combination, alongside standard chemotherapy in women with newly diagnosed breast cancer at high risk of early recurrence. By studying the genetic signature of the tumors, the researchers hoped to more precisely identify subgroups of patients who would respond to particular treatments.

“This will allow us to tailor treatment further so that the right anticancer [treatments] can be given to the right patients who have the highest chance of response, and so that patients who are unlikely to respond can be prioritized to receive another therapy,” said Dr. van ‘t Veer.

MammaPrint Test

In the first part of her presentation at the meeting (Abstract 2), Dr. van ‘t Veer described how refining information from the MammaPrint test, which looks at the activity of 70 genes in breast cancer tissue, provided information on how tumors would respond to the treatments, depending on whether it classified the patients as high-risk (MP1) or ultra–high-risk (MP2).

“MammaPrint is a prognostic signature used to predict the likelihood of a patient experiencing an early recurrence of her breast cancer in the absence of chemotherapy. In this study we tested the hypothesis that MP1/2 status is associated with tumor response, and we looked to see whether any association might depend on hormone or HER2 receptor status, as well as the treatment regimen the patients were receiving,” said Dr. van ‘t Veer.

“We found that, as hypothesized, the … MP2 patients had higher rates of complete pathologic response than the lower-risk MP1 patients.”
A total of 483 (49%) of the 986 patients were identified as being MP2, and they were 2.62 times more likely to have a pathologic complete response compared to MP1 patients. When the results were adjusted according to which treatment they had received, and whether or not their cancer was driven by hormones or HER2 receptors, the pathologic complete response rate for MP2 patients was 2.43 times higher than that of MP1 patients.

Further analysis according to which treatments they were receiving showed that MP2 patients were more likely to achieve pathologic complete response if they were taking veliparib/carboplatin, neratinib (Nerlynx), ganitumab, ado-trastuzumab emtansine (Kadcyla)/pertuzumab (Perjeta), or pembrolizumab (Keytruda) in addition to the standard paclitaxel treatment alone or in combination with trastuzumab (Herceptin). Analysis of responses according to types of receptors showed that MP2 patients with cancers that were hormone receptor (HR)–positive and HER2-positive were 3.62 times more likely to achieve pathologic complete response than MP1 patients, while those who with HR-positive, HER2-negative disease were 3.2 times more likely to achieve pathologic complete response compared to MP1 patients. This was not found in patients with HR-positive, HER2-negative disease.

“The most basic message of this study is that a prognostic signature that predicts good outcome in patients with a low-risk signature when forgoing chemotherapy can also, when further stratified, be used to predict response in high-risk signature patients who receive chemotherapy or targeted therapies. In short, this is a prognostic signature that is also predictive. The clinical implications will need to be further developed, but these data suggest that MP1/2 status might be a useful adjunct in predicting which patients are likely to respond to which drugs or combinations,” said Dr. van ‘t Veer.

BluePrint Test

In the second part of her presentations from I-SPY 2 (Abstract 3), Dr. van ‘t Veer described how the BluePrint 80-gene signature test was used to classify 375 patients with HR-positive, HER2-negative disease by biologic subtype, as having either basal, luminal, or HER2-subtype breast cancer. Dr. van ‘t Veer and her team hypothesized that HR-positive, HER2-negative tumors classified as basal by BluePrint would be more responsive to targeted chemotherapy than the more typical luminal cancers. 

“This analysis showed that patients with HR-positive, HER2-negative breast cancers of basal subtype as assessed by BluePrint were more likely to achieve a pathologic complete response than patients with luminal-type breast cancers. In addition, we showed that though patients with luminal cancers were less likely to respond with a pathologic complete response, nonresponding patients with HR-positive, HER2-negative luminal [disease] had superior long-term survival outcomes compared to nonresponding patients with HR-positive, HER2-negative basal [disease].”  

Patients with basal subtype cancers were approximately four times more likely to achieve pathologic complete response than patients with luminal cancer, regardless of which therapy they were receiving. In addition, the researchers found an association between subtype as assessed by BluePrint and the MammaPrint MP1 or MP2 classes; 77% of patients with the HR-positive, HER2-negative basal subtype were also ultra–high-risk MP2 types, compared to only 9% of HR-positive, HER2-negative luminal cases.

“These findings suggest that BluePrint can identify a subset of patients with HR-positive, HER2-negative basal tumors who are more likely to respond to neoadjuvant chemotherapy,” said Dr. van ‘t Veer. “The overlap between BluePrint basal subtype and MP2 class suggests that different predictive signatures may identify similar sets of patients who are most likely to respond to a particular investigational drug.” 

I-SPY 2 is ongoing and recruiting patients.

Disclosure: See study authors’ full disclosures at ecco-org.eu.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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