BluePrint Subtyping May Predict Benefit of Adjuvant Pertuzumab in Early Breast Cancer

Ian E. Krop, MD, PhD

Adjuvant treatment with pertuzumab (Perjeta) demonstrated a trend for greater benefit in patients with early breast cancer with a HER2 single-activated pathway determined by molecular subtyping using BluePrint assay, according to an exploratory analysis of the APHINITY study presented during the 2020 San Antonio Breast Cancer Symposium.¹

Investigators also found, in this trial in which all cancers were pathologically confirmed to be HER2 positive, BluePrint’s single activated basal subtype showed a significantly worse prognosis than other single activated subtypes.

“Based on predictive analysis, there was a trend of greater benefit with the addition of pertuzumab to trastuzumab (Herceptin) in patients with BluePrint HER2 single-activated tumors compared with other groups,” Ian E. Krop, MD, PhD, said during the poster presentation. Krop is associate chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, and clinical research director of the Breast Oncology Center at Dana-Farber Cancer Institute, as well as an associate professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

BluePrint, an 80-gene molecular subtyping test, classifies early breast cancer into RNA-based functional molecular subtypes—basal, luminal, and HER2—according to gene expression.² The test evaluates the functionality of receptor cell signaling and complements immunohistochemistry and fluorescence in situ hybridization, providing information regarding patient chemotherapy or hormonotherapy resistance for more informed treatment decision-making.

Study investigators hypothesized that BluePrint could identify a subgroup of patients who would derived further benefit from the addition of pertuzumab to chemotherapy/trastuzumab from the population of those evaluated in the phase 3 APHINITY trial (NCT01358877). Pertuzumab is approved to treat patients with early breast cancer in combination with chemotherapy and trastuzumab.³

In total 4805 patients with histologically confirmed HER2-positive early breast cancer were treated with standard adjuvant chemotherapy and trastuzumab plus either pertuzumab or placebo for 1 year. With a median follow up of 45 months, the primary analysis showed significant invasive disease-free survival (iDFS) benefit for the addition of pertuzumab to chemotherapy and trastuzumab at 3 years with a hazard ratio of 0.81 (95% CI, 0.66-1.00; P = 0.045).¹

BluePrint analysis was performed using RNA sequencing data from a subset of APHINITY samples (N = 969) with usable BluePrint subtyping. Investigators found that 50% of the cancers were classified as luminal subtype (N = 485), 28% of HER2 subtype (N = 275), and 22% as basal (N = 210). Patients’ tumors were further classified as single-activated or dual-activated. Single activated subtype was seen in 123 patients of 210 patients (59%) in the basal subtype, 413 patients of 485 patients (85%) luminal subtype, and 139 patients of 275 patients (51%) of HER2 subtype cancers.

A majority of patients in all BluePrint groups were lymph-node positive, over 35 years old, and received an anthracycline containing regimen. Most patients in the luminal group were HR positive whereas a majority of BP basal and BP HER2patients were HR negative.

A greater benefit with the addition of pertuzumab to chemotherapy/trastuzumab was suggested in the single activated HER2 subtype compared with other groups—single HER2 HR was 0.56 (95% CI, 0.27-1.15), single basal HR was 0.89 (95% CI, 0.44-1.79) and single luminal HR was 0.93 (95% CI, 0.61-1.41).

“While most cancers have 1 activated functional BluePrint pathway, some cancers may display 2 functionally activated BluePrint pathways, Krop said.

Research is ongoing to confirm these findings and to further define the role of BluePrint in the characterization of HER2 positive cancers.

_References

_{1. Krop IE, Mittempergher L, Paulson JN, Andre F, et al. Prediction of benefit from adjuvant pertuzumab by BluePrint RNA sequencing in the APHINITY trial. Poster presented at: 2020 San Antonio Breast Cancer Symposium; December 9, 2020. Abstract PD3-01. Accessed December 10 2020. https://bit.ly/39VKQaI}

_{2. Agendia BluePrint. Agendia Precision Oncology. Accessed December 10, 2020. https://bit.ly/39Y7Fuk}

_{3. Perjeta. Prescribing information. Genentech; 2020. Accessed December 10, 2020. https://bit.ly/3m56D27}