Two tests that analyze the genetic signature of tumors were able to identify which drug treatments would be most optimal for certain breast cancer patients. A symposium on molecular targets and cancer therapeutics in Dublin featured these results, part of a long-running clinical study known as the I-SPY 2 TRIAL.

"Effective breast cancer treatment depends on recognizing the biology of the tumor. MammaPrint and BluePrint are two tests that recognize disease that is at risk of early recurrence and the different molecular subtypes,” said Laura van ‘t Veer, PhD, an investigator with I-SPY and leader of the Breast Oncology Program at the University of California San Francisco during the symposium hosted by the European Organization for Research and Treatment of Cancer, the National Cancer Institute, and the American Association for Cancer Research. 

Since 2010 the $26.5 million I-SPY 2 trial has been evaluating the effects of adding novel agents to standard chemotherapy in the neoadjuvant setting, to see if it improves outcomes in women with high-risk, fast-growing breast cancer. As CLN reported in 2013, the ongoing trial seeks to inform investigators in real time as it produces results and new information. The goal is to determine which therapies work best with specific cancer types while advancing evidence around biomarkers, directing some toward eventual use in clinical practice. “This will allow us to tailor treatment further so that the right anti-cancer drugs 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 van ‘t Veer.

MammaPrint assesses the activity of 70 genes in breast cancer tissue to predict whether early recurrence of breast cancer will take place in absence of chemotherapy. In the study, investigators leveraged this technology to test a hypothesis: that “high risk” (MP1) or “ultra-high risk” (MP2) status was associated with tumor response. “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 van ’t Veer.

“We found that, as hypothesized, the ‘ultra-high risk’ MP2 patients had higher rates of complete pathologic response than the lower risk, MP1 patients,” she added. Among 986 patients, 483 identified as MP2 were 2.62 times more likely than the MP1 patients to see their tumors fully disappear—a phenomenon known as pathologic complete response (pCR). Additionally, investigators found that the pCR rate for MP2 patients was 2.43 times higher than that of MP1 patients once they adjusted results based on type of treatment received, and source of cancer (hormones or HER2 receptors).

The researchers also discovered that tumors in MP2 patients taking veliparib/carboplatin, neratinib, ganitumab, TDM1/pertuzumab or pembrolizumab as well as standard paclitaxel treatment alone or in combination with trastuzumab, were more likely to disappear. Looking at the results by receptor type, MP2 patients with hormone receptor positive (HR+) and HER2 positive (HER2+) cancers and HR+ and HER2- were much more likely to achieve pCR compared with MP1 patients, although this wasn’t true for HR- HER+ patients.

“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,” according to van ’t Veer. The findings also suggest that MP1/2 status might be useful in predicting drug response in patients, she added.

Investigators subsequently used the BluePrint 80-gene signature test to classify 375 HR+HER2- patients by basal, luminal, or HER2 subtype breast cancer subtypes. Specifically, van ’t Veer wanted to see if HR+HER2- tumors the test classified as basal would respond more successfully to targeted chemotherapy than the more typical luminal cancers.

"This analysis showed that patients with HR+HER2- breast cancers of basal subtype as assessed by BluePrint were more likely to achieve a complete pathologic 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 complete pathologic response, nonresponding HR+HER2- luminal patients had superior long-term survival outcomes compared to nonresponding HR+HER2- basal patients,” she summarized.

Investigators also found an association between the subtypes analyzed by BluePrint and the MammaPrint MP1 or MP2 classes.

Overall, 77% of the HR+HER2- basal patients were also MP2 types, compared with 9% of HR+HER2- luminal patients. “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,” van ‘t Veer said.