Molecular Subtyping Identifies Chemosensitivity in Breast Cancer Patients

More accurate identification of molecular subtyping for breast cancer may be able to identify patients with chemosensitivity to specific therapies, according to a new study.

The aim of the prospective Neoadjuvant Breast Registry - Symphony Trial (NBRST) was to compare chemosensitivity as defined by pathological complete response using the 80-gene BluePrint functional subtype profile versus conventional immunohistochemistry (IHC)/fluorescence in situ hybridization (FISH) subtyping.

The 80-gene BluePrint subtype was developed based on 200 tumors in which the mRNA expression matched the protein expression, “suggesting the associated cellular molecular regulatory pathways were intact or active,” lead author Pat W. Whitworth, MD, Director, Nashville Breast Center in Nashville,Tenn., said in an interview.

“In contrast the intrinsic subtypes originally identified were based purely on mRNA patterns without regard to protein expression.”

Dr. Whitworth presented the results of the study on Friday, September 25, 2015 at the 2015 American Society of Clinical Oncology (ASCO) Breast Cancer Symposium in San Francisco (Abstract 114).

One major question for the phase IV NBRST study was whether functional subtypes reflected tumor biology in ways that correlated well with treatment response.

“The study findings show that functional (80-gene BluePrint) subtype corresponds with neoadjuvant treatment response better than conventional (IHC/FISH) subtype categories,” said Whitworth. He noted that no direct comparison to intrinsic subtype has been conducted.

He reported three major findings. “Overall, functional subtyping reclassifies about one in five tumors. Functional subtype prediction of neoadjuvant treatment response is significantly superior compared to all conventional IHC/FISH categories. Approximately one-third of all HER2 FISH-positive tumors are functional (80-gene BluePrint) luminal subtype.”

Surprisingly, he said the HER2 FISH-positive BluePrint luminal subtype is resistant to chemotherapy plus trastuzumab (Herceptin) and sensitive to chemotherapy plus trastuzumab plus pertuzumab (Perjeta).

These findings suggest that high-risk patients being treated in the adjuvant setting will benefit from the addition of pertuzumab to chemotherapy plus trastuzumab.

“They also suggest clinical trials evaluating the benefit of pertuzumab, and dual HER2 targeting in general, will be best designed and interpreted taking the 80-gene subtype into account,” he said.

Novel findings from phase IV studies like this should be confirmed in other phase IV studies, Whitworth said, “or even better, using blocks from phase III trials, or even better as a part of upcoming phase III trials. This last option is the most costly and least practical, but the most compelling. With all the interest and clinical trial activity around HER2 targeting, it should be possible as a nested or stratification component.”

In the meantime, Whitworth suggests that clinicians may be able to use these phase IV findings “to support coverage for pertuzumab in the adjuvant setting when deemed important by the oncologist.”