ONCAlert | 2018 ASCO Annual Meeting
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Results Show HER2 Mutations Cause Endocrine Resistance in ER+ Breast Cancer

Jason M. Broderick
Published Online:1:20 PM, Mon March 19, 2018

Elaine R. Mardis, PhD
According to the findings reported during a media preview for the 2018 AACR Annual Meeting, acquired HER2 mutations cause endocrine resistance in some patients with ER-positive/HER2-negative breast cancer.

Researchers discovered that this resistance could be overcome by a dual targeting strategy that combines the hormone therapy fulvestrant (Faslodex) and the HER2 kinase inhibitor neratinib (Nerlynx).

“Activating HER2 mutations are a distinct mechanism of acquired resistance to multiple types of anti-ER therapy in ER-positive metastatic breast cancer. Moreover,these mutations can be overcome by treatment with an irreversible HER2 inhibitor,” said Uttara Nayar, PhD, co-lead author and a research fellow in medicine at Dana-Farber Cancer Institute, Harvard Medical School.

Nayar said endocrine resistance is the most frequent cause of breast cancer mortality in the country, but a greater understanding of the underlying mechanisms causing resistance to hormone therapy is necessary beyond the ER mutations in 25% to 30% of these patients.

Nayar and colleagues sought to identify mechanisms of resistance by using whole exome sequencing in patients with ER+ metastatic breast cancer who had become resistant to ER-targeting agents such as tamoxifen, fulvestrant, and aromatase inhibitors (AIs).

HER2 mutations were found in 12 of 168 metastatic biopsies. 8 mutations were known to be activating. According to an assessment of biopsies available at baseline, 4 out of 5 patients with activating mutations had no evidence of HER2 baseline mutations. This suggests that they emerged due to ER-directed treatment.

The mutations, tested in the lab using functional assays, showed that, “The activating mutations identified in this study conferred strong resistance to aromatase inhibitors," Nayar explained. “In addition, and in contrast to ER mutations, these HER2 mutations resulted in resistance to tamoxifen, fulvestrant, and the CDK4/6 inhibitor palbociclib."

In vitro assays demonstrated that resistance caused by all 4 mutations was overcome by combining ER-directed therapy with the irreversible HER2 kinase inhibitor neratinib. This suggests a novel effective treatment strategy in these patients.

Nayar reported that the laboratory findings translated to the clinic. She described one patient who, after being diagnosed in 2011 with stage 2 ER-positive, PR/HER2-negative breast cancer, was treated with tamoxifen. In 2015, it was discovered that the patient had metastatic disease with an activating HER2 V777L mutation and an activating PI3CA E545K mutation. This particular patient responded to the combination of fulvestrant and neratinib.

When asked about potential future steps, Nayar said, “In the future, we hope to be able to develop upfront combinations that can preempt the emergence of HER2 mutations in tumors, ultimately enabling us to deliver more durable responses and better precision medicine in ER+ metastatic breast cancer.”

Moderator Elaine R. Mardis, PhD, co-executive director of the Institute for Genomic Medicine at Nationwide Children’s Hospital, commented on these findings as well, saying, “Part of the importance of this study is that it has revealed, using next-generation sequencing technology, and the ability to look at a disease, not only pre, but also post the development of resistance to estrogen agonists, a new mechanism for escaping the effect of those drugs. And, excitingly, these HER2 point mutations have effective small molecule inhibitors, such as neratinib.”

Previously, the discovery of crosstalk between the HER2 and hormone receptor pathways led to the treatment strategy of dual targeting regimens in patients presenting with HER2+/HR+ breast cancer.

355 women were randomized in the phase III ALTERNATIVE trial with HER2+/HR+ breast cancer to lapatinib (Tykerb) plus trastuzumab (Herceptin) and an AI (n = 120), trastuzumab plus an AI (n = 117), or lapatinib plus an AI (n = 118). Median progression-free survival (PFS) was 11 months for women assigned to lapatinib/trastuzumab plus an AI compared with 5.7 months for patients assigned to trastuzumab plus an AI (HR, 0.62; = .0064). The median PFS was 8.3 months for the lapatinib/AI arm.

IN the phase II PERTAIN trial, 258 postmenopausal women with HER2-positive, HR-positive locally advanced or metastatic breast cancer were randomized to receive pertuzumab (Perjeta) with trastuzumab (n= 129) or trastuzumab alone (n = 129) in combination with an AI. Based on the discretion of the investigator, induction chemotherapy could be given for 18 to 24 weeks prior to starting endocrine therapy.

Median PFS was 18.89 months with the pertuzumab triplet compared with 15.80 months for trastuzumab and an AI alone (HR, 0.65; P = .0070). For patients with measurable disease, ORR with the pertuzumab combination was 63.3% compared with 55.7% for trastuzumab and an AI alone.

Published in The Lancet Oncology, one study suggests that the next step might be not only dual targeting, but trying to enhance the impact of endocrine therapy by adding a CDK4/6 inhibitor as well.

The phase II NA-PHER2 study enrolled 36 patients with previously untreated, histologically confirmed, unilateral, invasive, ER-positive/HER2-positive cancer. 30 patients were included in first endpoint analysis.

The study showed that the neoadjuvant combination of palbociclib (Ibrance), pertuzumab, fulvestrant, and trastuzumab had a high clinical response. 29 of 30 (97%) patients showed a response, including 15 patients who had complete responses and 14 patients with partial responses.
 
 
Reference:
Nayar U, Cohen O, Kapstad C, et al. Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to ER-directed therapies. 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, IL.


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