Biomarker analysis predicts response to adjuvant trastuzumab, pertuzumab in HER2+ breast cancer

Medical writer: Leah Lawrence

A comprehensive genomic analysis of women with HER2-positive breast cancer enrolled in the APHINITY trial revealed several markers that may be associated with better prognosis and increased benefit from treatment with trastuzumab and pertuzumab (Abstract 1012).

Ian E. Krop, MD, PhD, of the Dana-Farber Cancer Institute, presented results of the analysis, which included DNA sequencing, RNA sequencing, tumour-infiltrating lymphocyte (TIL) analysis, and HER2 immunohistochemistry and FISH, during the “Targeting Breast Cancer: Breaking the Code” Clinical Science Symposium held June 1.

APHINITY was a phase III study investigating the benefit of adjuvant therapy with pertuzumab when added to trastuzumab and chemotherapy in women with HER2-positive early-stage breast cancer. The trial demonstrated an invasive disease-free survival benefit to adding pertuzumab, but the overall magnitude was relatively small at only 1.7% difference at 4 years, Dr. Krop said.

In high-risk populations, such as patients with node-positive or hormone receptor–negative disease, the benefit was somewhat greater, but Dr. Krop and colleagues wanted to elucidate biomarkers to identify subgroups of patients that might benefit even more from the added treatment.

The DNA and RNA testing occurred within a nested case control study including 299 patients with an invasive disease-free survival event who were matched 1:3 with an event-free control group of 1,023 patients. TIL analysis occurred in 4,313 patients, and HER2 analysis occurred in 4,804 patients of the intention-to-treat population from the APHINITY trial.

The DNA analysis revealed that PI3K pathway alterations (i.e., PI3K/PTEN/AKT alterations) occurred in 37% of patients and was associated with a worse outcome (HR 1.35, 95% CI [1.01, 1.79]; P = 0.04). According to Dr. Krop, there was a modest trend toward decreased benefit of pertuzumab seen in patients with PI3K pathway alterations, but it was not statistically significant.

MYC (HR 1.61, 95% CI [1.16, 2.23]; P = 0.00) and ZNF703 (HR 1.62, 95% CI [1.07, 2.47]; P = 0.02) amplification was associated with worse prognosis. In contrast, TOP2A amplification (HR 0.49, 95% CI [0.32, 0.74]; P = 0.00) was associated with a better prognosis, independent of anthracycline use.

RNA sequencing showed the luminal A subtype was associated with better outcomes, particularly compared with patients with basal subtype (HR 3.11, 95% CI [1.44, 6.6]; P = 0.003). There was no significant interaction observed between PAM50 subtype and pertuzumab benefit.

High levels of certain immune markers were also associated with favorable prognosis and predicted pertuzumab benefit. A three-gene T-cell immune signature consisting of IFNG PD-L1, and CXCL9 (HR 0.68, 95% CI [0.52, 0.89]; P = 0.005) and its individual components appeared to be associated with favorable outcomes. No link between the T-cell immune signature and pertuzumab benefit was found; however, higher levels of the individual component genes appeared to predict greater benefit of the drug (CXCL9 > 75%, P = 0.05; IFNG > 75%, P = 0.03).

Higher TIL levels, taken as a continuous variable, were also associated with favorable outcomes in a prognostic analysis (HR 0.91, 95% CI [0.86, 0.96]; P = 0.001). Patients with TIL levels in the highest quartile appeared to also derive benefit from pertuzumab in a predictive analysis (HR 0.35, 95% CI [0.19, 0.65]; P = 0.003).

Finally, the HER2 analyses showed that cancers with high HER2 copy number (≥ 6) had better prognosis (HR 0.68, 95% CI [0.50, 0.91]; P = 0.01) and may be predictive of greater benefit with pertuzumab (HR 0.75, 95% CI [0.60, 0.93]; P = 0.04).

“While we identified a number of predictive markers, none were so strong that we could use them in clinic to say which patients would benefit from pertuzumab and which would not, but we certainly identified some directions worth exploring,” Dr. Krop said.

Discussant Matthew P. Goetz, MD, of Mayo Clinic, congratulated the authors on the important study, calling it a “tour de force.”

“This study is incredibly important because it is a large international study, but also because the researchers were able to get biomarker analyses for over 1,000 patients, which, as far as I know, is certainly one of the largest analyses in the adjuvant HER2 setting,” Dr. Goetz told ASCO Daily News.

The path forward for optimization of HER2-targeted therapies, according to Dr. Goetz, is clinical research focusing on using tissue and imaging biomarkers, de-escalation of therapy when possible to reduce chemotherapy without altering efficacy, and escalation of therapy based on biology and initial response to anti-HER2–based therapy.



Posted on 15 July 201925 March 2021