HER2+ Breast Cancer Heterogeneity Calls for Combos

Adam M. Brufsky, MD, PhD,

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^® Peer Exchange^® 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.

Early-stage Disease

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 and clinical² 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.

The panelists agreed that trastuzumab should be considered for all patients with early-stage HER2-positive disease in the neoadjuvant setting, even if the PAM50 assay or 70-gene assays predict low therapeutic response or low genomic risk, respectively. Robson noted that the ability of multigenomic assays to predict chemotherapy benefit is limited, and Aditya Bardia, MBBS, MPH, stated that, considering the low toxicity of trastuzumab, “you need to have a very strong reason not to give it.”

Extended Therapy With Neratinib

Blackwell also noted that the importance of preventing recurrence is worth the risk of over- treating an early-stage, low-risk tumor. “To be quite honest, there are doctors out there who are getting sued because they did not offer trastuzumab for [an early-stage HER2-positive cancer] and the cancer comes back,” she said.Extended adjuvant therapy with neratinib, a tyrosine kinase inhibitor of HER1, HER2, and HER4, has demonstrated clinical activity in patients with HER2-positive metastatic breast cancer, even in those with prior exposure to other anti-HER2 agents and taxane-based chemotherapy.⁶ The ExteNET trial⁷ showed that 12 months of neratinib significantly improved 2-year disease-free survival (93.9% vs 91.6% with placebo) in patients with early-stage HER2-positive breast cancer who had completed trastuzumab-based neoadjuvant and adjuvant therapy less than 2 years prior to trial enrollment.

Bardia also noted that the subgroup with ER-positive disease showed a notable improvement in outcomes with neratinib, but he and Robson stated that these patients may be reluctant to take another agent in addition to extended endocrine therapy, especially after a lengthy regimen of chemotherapy plus HER2-targeted therapy. However, Blackwell stated that adding neratinib to extended endocrine therapy should be discussed with all patients with triple-positive disease, even those predicted to have low-risk tumors, if further data continue to show similar or improved survival with neratinib. “Our job is to help [patients] participate in these decisions. I’m going to have plenty of patients who say ‘you’ve got to be crazy,’ but I will feel obliged to at least discuss it and document it in my note,” she said.

Diarrhea was the most common adverse event in the ExteNET trial, with grade 3 diarrhea reported in 40% of the group receiving neratinib. However, early prophylaxis and diligent monitoring can often reduce the severity of diarrhea enough to make neratinib tolerable for most patients, according to Blackwell. The CONTROL (PUMA-NER-6201) study,⁸ an open-label phase II trial, showed that prophylaxis with loperamide reduced the incidence of neratinib-induced diarrhea, and a preliminary analysis of an expansion group of patients suggested that loperamide and budesonide may further reduce diarrhea incidence.

Based on their clinical practice experiences, the panelists predicted that recommendations for extended therapy with neratinib would depend in part on the patient’s initial presentation. For those with small, node-negative, HER2-positive tumors who are 96% to 98% likely to survive free of disease with a year’s worth of trastuzumab, it would be hard to make a strong case for extended therapy with neratinib, said Robson. He and Blackwell agreed that the extended therapy likely would be more suitable for patients with large “HER2- addicted” tumors and node-positive disease that responds well to the initial regimen of HER2-targeted therapy.

Metastatic Disease

However, Blackwell stated that with the current uncertainty of the clinical benefits, she tends to err on the side of overtreatment, provided the patient can physically and financially tolerate the medication and the therapy does not definitively reduce duration of survival. “For that individual patient sitting in front of me, I want to be able to say ‘we’ve done everything within reason to prevent your breast cancer from coming back.’”Data from the CLEOPATRA study⁹ suggested that blockade of the HER2 signaling pathway with multiple agents improves outcomes for locally recurrent, unresectable, or metastatic HER2-positive breast cancer. Follow-up data at a median of 50 months showed that the addition of pertuzumab to first-line therapy with trastuzumab and docetaxel improved median overall survival by 15.7 months over trastuzumab, docetaxel, and placebo.

Patients with locally advanced or metastatic triple-positive disease may not bene t as much from this combination if inhibition of the HER2 pathway enhances ER signaling, according to Blackwell. Thus, the PERTAIN study¹⁰ aimed to investigate whether addition of endocrine therapy improved response to dual HER2 blockade in postmenopausal patients with HR-positive and HER2-positive locally advanced metastatic breast cancer. This open-label, phase II trial randomized participants 1:1 to receive pertuzumab, trastuzumab, and an AI or trastuzumab and an AI. Some patients also received induction chemotherapy with docetaxel or paclitaxel at the investigator’s discretion 18 to 24 weeks before starting the AI/anti-HER2 therapy. A primary analysis showed that median progression-free survival (PFS) was longer with the pertuzumab/trastuzumab/AI regimen than with trastuzumab/AI therapy (18.9 vs 15.8 months) and was generally well-tolerated.

Improving Treatment

According to Blackwell, these results further support her practice of adding the AI therapy after chemotherapy in patients with triple-positive disease. Bardia suggested that combining the AI with the anti-HER2 agents (pertuzumab and trastuzumab) after induction chemotherapy may be more effective than combining endocrine therapy with chemotherapy, as was done in the B-52 study. However, the panelists cautioned against directly comparing the B-52 and PERTAIN studies due to the differences in patient population (nonmetastatic vs metastatic disease) and primary outcome measures (pCR vs PFS), and indicated the need for additional research on treatment sequences.Overall, the panelists concluded that recent combinations of chemotherapy and targeted anti-HER2 agents will continue to improve outcomes in patients with HER2-positive breast cancer. However, they indicated that the high heterogeneity of patients due to expansion of criteria for HER2-positive disease means that methods to improve patient classification will be necessary to predict response to anti-HER2-targeted therapies.

In addition, the panelists indicated that optimizing the sequence of chemotherapy, endocrine therapy, and HER2-targeted therapy for patients with triple-positive breast cancer will require further research to clarify the crosstalk between the ER and HER2 signaling pathways. “The number of lectures I go to in any given month about how ER has cross- talked with the HER2 pathway—you can come up with almost any story,” said Blackwell. “This is going to be relevant not only in the metastatic setting but also in the early-stage setting.” She said that increased development of and participation in clinical trials for all stages of disease will help improve predictive assays and treatment for all subtypes of early-stage and metastatic HER2- positive disease.

References

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