Adam M. Brufsky, MD, PhD
Targeted therapies have improved outcomes for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, which is characterized by an aggressive tumor phenotype and lower overall survival. However, questions remain on how to predict which patients will benefit from neoadjuvant or extended HER2-targeted therapies and how to treat patients with triple-positive (estrogen receptor [ER]-, progesterone receptor-, and HER2-positive) breast cancer, according to experts who participated in a recent OncLive®
panel moderated by Adam M. Brufsky, MD, PhD.
Expansion of pathologic criteria has increased the number and heterogeneity of patients with HER2-positive disease. Although the panelists acknowledged that the expanded criteria help identify more patients who may benefit from anti- HER2 therapies, the criteria may also include patients with tumors driven by non-HER2 factors who may not respond to HER2-targeted therapy. The panelists also discussed the crosstalk between the ER and HER2 signaling pathways that occurs with triple-positive disease and how treatment requires strategic combinations and sequences of chemotherapy, HER2-targeted therapy, and endocrine-based therapies to prevent the treatment resistance that occurs from targeting a single pathway.
The panel also discussed genomic assays that could predict which subtypes of patients would bene t from anti-HER2-targeted therapies and the benefits and drawbacks of extended anti-HER2 therapy with neratinib.
Chemotherapy combined with anti-HER2 agents used to be the first-line option for HER2-positive breast cancer, regardless of hormone receptor (HR) status. However, preclinical1
studies have suggested that anti-HER2 treatment alone could lead to treatment resistance via enhanced signaling through the ER pathway. An analysis showed that in patients with metastatic HER2-positive disease, ER expression in more than 30% of cancer cells significantly predicted a lower probability of response to chemotherapy plus trastuzumab, an HER2-targeting antibody.3
Thus, researchers have pursued adding endocrine therapy to chemotherapy and HER2-targeted therapy to prevent treatment resistance in patients with triple-positive disease.
The NRG Oncology/NSABP B-52 phase III trial4
randomized patients with locally advanced, nonmetastatic HR- and HER2-positive breast cancer to receive an aromatase inhibitor (AI) (premenopausal women also received estrogen deprivation therapy) or placebo in addition to neoadjuvant chemotherapy/HER2-targeted therapy consisting of docetaxel, carboplatin, trastuzumab (Herceptin), and pertuzumab (Perjeta). The addition of endocrine therapy did not significantly improve the rate of pathologic complete response (pCR), although the study investigators noted that giving the endocrine therapy with the neoadjuvant therapy was not antagonistic and did not increase toxicity.
Kimberly L. Blackwell, MD, pointed out that although the lack of benefit with endocrine therapy was disappointing, she was optimistic about the findings showing that the estrogen depletion and administration of luteinizing-hormone releasing hormone agonist, often used for women who wish to preserve ovarian function, did not decrease the pCR rate or interfere with therapeutic response to the chemotherapy/HER2-targeted therapy combination. She indicated that the results reflect the need for further research on the interaction between ER and HER2 signaling, stating that the communication between ER and HER2 pathways is “one of the biggest black boxes in breast cancer biology.”
However, Mark E. Robson, MD, pointed out that the high heterogeneity among patients, even within the triple-positive cohort, makes it challenging to predict response to chemotherapy because tumor growth may not be driven by the HER2 path- way. “Over the years, we’ve expanded our definition of HER2 positivity from the pathology standpoint to avoid missing people who could potentially benefit from anti-HER2 therapy or HER2-directed therapies,” he said. “But, in doing so, we may well have cast a net to include people who aren’t going to benefit because their tumors aren’t really HER2-driven.”
Robson went on to summarize the PAMELA study,5
which used the PAM50 assay to predict which intrinsic breast cancer subtypes (luminal A, luminal B, HER2-enriched, basal-like, and normal-like) would benefit from 18 weeks of dual HER2 blockade with lapatinib (Tykerb) and trastuzumab. He noted that individuals with a HER2-enriched subtype (about 60% of the study participants) were more likely to benefit from dual anti-HER2 treatment (with or without endocrine therapies) in the neoadjuvant setting.