Javier Cortés, MD, PhD

The invited discussant of the updated APHINITY data was Javier Cortés, MD, PhD, Head of the International Breast Cancer Center in Barcelona.

“I think we clearly learned two things from the data. One is that estrogen receptor positivity does not matter in terms of benefit from the addition of pertuzumab. There is a very similar absolute benefit and a very similar hazard ratio. It does not play a role. And second, we should clearly discriminate between node-positive and node-negative disease [in using pertuzumab],” said Dr. Cortés.

In the third interim analysis of APHINITY, overall survival was numerically higher for HER2-positive patients treated adjuvantly with both pertuzumab and trastuzumab, though statistical significance was not reached (P = .078). Invasive disease–free survival, in the preplanned exploratory analysis, was improved by an absolute 2.6% with the addition of pertuzumab. In patients with positive lymph nodes, overall survival increased by an absolute 1.9% (HR = 0.80), and invasive disease–free survival increased by 4.9% (HR = 0.72).

The magnitude of benefit is comparable to that achieved by aromatase inhibitors over tamoxifen. In the Early Breast Cancer Trialists’ Collaborative Group trial,¹ aromatase inhibitors conveyed an absolute 2.7% benefit in overall survival (HR = 0.89) and a 2.1% increase in breast cancer–specific survival (HR = 0.85). “It’s true the P value was significant in the endocrine therapy trials, but the number of patients was about 10,000, compared with about 3,000 node-positive patients in APHINITY,” he noted.

‘Is More Always Better?’

When considering adding one good treatment atop another, the question then becomes, “Is more always better?” he said. “It is very clear, in my opinion, that in the node-positive cohort more is better. But in the node-negative cohort (certainly for patients with small tumors), adding anything else to trastuzumab may not be better.”

However, he added, this does not mean that all node-negative patients should be excluded from dual HER2 blockade: “We need better selection of high-risk vs low-risk patients,” he added. A biomarker analysis from APHINITY is attempting to identify risk groups according to PI3K pathway activation, HER2 expression levels, PAM50 subtypes, T-cell immune signature and immune gene markers, copy number amplifications, and levels of tumor-infiltrating lymphocytes.

Dr. Cortés is already assessing individual risk in HER2-positive patients using the HER2DX genomic test. The assay measures the RNA expression of 27 genes and creates four gene signatures based on levels of immune cells, HER2 amplicon, cell proliferation, and luminal differentiation. A risk score is generated based on the gene signatures plus tumor and nodal information, and this can differentiate good from poor prognosis.

He described how he used this test to guide treatment for a 54-year-old woman with a 45-mm hormone receptor–negative cT2N0M0 grade 2 intraductal carcinoma who had already undergone a bilateral mastectomy. The HER2DX result indicated high risk. Dr. Cortés believed this warranted the addition of pertuzumab to trastuzumab and chemotherapy, despite APHINITY’s finding that node-negative patients do not benefit from this approach.

Adjuvant vs Neoadjuvant Treatment

Had the patient undergone neoadjuvant therapy, her prognosis may have been clearer. Response to neoadjuvant treatment is the best way to predict prognosis, escalate treatment if necessary, and improve long-term outcomes, Dr. Cortés emphasized.

“Can we select a bad-prognosis population for whom we might escalate treatment? Clearly, we can, if we go for neoadjuvant treatment, based on achieving a pathologic complete response. We can’t do that if we go with the APHINITY [adjuvant] strategy,” he pointed out.

Integration of neoadjuvant therapy, assessment of response, and genomic signatures or other biomarkers will be the best way to achieve the highest absolute treatment benefits from treatment, he said. 

DISCLOSURE: Dr. Cortés disclosed financial relationships with Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, HiberCell, BioInvent, Genmab, Gilead, Menarini, Zymeworks, Reveal Genomics, Eisai, Pfizer, Samsung Bioepis, MedSIR, Nektar, and Gilead.

REFERENCE

1. Early Breast Cancer Trialists’ Collaborative Group: Aromatase inhibitors versus tamoxifen in early breast cancer: Patient-level meta-analysis of the randomised trials. Lancet 386:1341-1352, 2015.