San Francisco, CA—A new genetic test may allow clinicians to improve their therapy decisions by better categorizing patients into specific subtypes compared with conventional immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) subtyping. According to data presented at the 2015 Breast Cancer Symposium, the BluePrint 80-gene assay reclassifies approximately 23% of tumors, allowing for more effective therapy selection, particularly in patients with triple-positive (HER2-positive/hormone receptor–positive) disease.
“Compared to conventional IHC/FISH, BluePrint functional subtyping reclassifies about 1 in 5 tumors, yielding significantly better correlation with both neoadjuvant chemotherapy responsiveness and resistance,” said Peter D. Beitsch, MD, Chief Physician, Dallas Surgical Group. “The 80-gene subtyping divided triple-positive cancers into 2 groups of almost equal size, 1 being luminal-driven and 1 being HER2-driven.”
Classification into molecular subtypes allows for more precise therapy selection for patients with breast cancer, and these subtypes have been shown to have distinct clinical outcomes.
The Neoadjuvant Breast Registry-Symphony Trial (NBRST) compared the multigene classifier with conventional IHC/FISH subtyping to predict chemosensitivity as defined by pathological complete response (pCR).
The researchers enrolled 889 patients with breast cancer from 62 US institutions. More than 90% of the patients had stage II or III disease. Overall, 66% of patients had hormone receptor–positive disease, 23% had triple-negative disease, and 29% had HER2-positive breast cancer.
This 80-gene assay divides breast cancer into luminal type, HER2-type, and basal-type tumors. The assay further divided luminal-type into luminal A and luminal B. All the assays were completed on a core biopsy up front.
The patients then received neoadjuvant chemotherapy or systemic endocrine therapy based on current guidelines. After surgery, the researchers reported the pCR of these patients, and they continue to follow the patients over time.
“A few patients received neoadjuvant endocrine therapy, but that was only 5% of the whole group,” Dr Beitsch observed. “This is really a neoadjuvant chemotherapy trial.”
Patients who were classified with HER2-positive disease received HER2-directed therapy with trastuzumab or trastuzumab plus pertuzumab.
Compared with conventional IHC and FISH subtyping, the assay reclassified 1 in 5 tumors. In the original luminal group, approximately 18% were reclassified into the basal group.
“We increased the basal group by 50% with molecular subtyping compared to immunostaining,” said Dr Beitsch, “but we maintained pCR rates in that group.”
The original basal group and the HER2-positive/hormone resistant–negative group basically remained the same, he noted. The biggest change was in patients with triple-positive disease—50% were HER2 subtype and 50% were luminal subtype.
“When we reclassified patients into ‘purer groups,’ the number of patients that were HER2-driven went down from 258 to 141, but the pCR rate actually increased considerably and was statistically significant,” Dr Beitsch reported.
The conundrum of patients with triple-positive disease having less responsiveness to trastuzumab and chemotherapy is well-documented, he said. When reclassified by subtype with the genetic test, however, the group that was classified as HER2 driven had nearly 50% pCR. By contrast, triple-positive patients who were molecularly subtyped into the luminal group were nonresponsive to neoadjuvant chemotherapy plus trastuzumab or trastuzumab alone.
“We solved the problem with triple-positive patients,” said Dr Beitsch. “They’re actually 2 different groups. There are almost equal numbers in the groups, but their response rates are remarkably different.”
Of note, a change in the standard of care during the course of the trial resulted in a significant increase in pCR in this previously unresponsive group.
“Pertuzumab overcame resistance to chemotherapy/trastuzumab in a substantial portion of the triple-positive/80-gene luminal subtype,” said Dr Beitsch. “When treated with chemotherapy and trastuzumab alone, there was almost no response. With the addition of pertuzumab, however, pCR increased 10-fold.”
