Acquired HER2 Mutations Cause Endocrine Resistance in ER+ Breast Cancer

Elaine R. Mardis, PhD

Acquired HER2 mutations cause endocrine resistance in some patients with ER+/HER2-negative breast cancer, according to findings reported during a media preview for the 2018 AACR Annual Meeting.

The researchers also found that this resistance could be overcome by a dual targeting strategy combining 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 explained that endocrine resistance is the most frequent cause of breast cancer mortality in the United States; however, beyond ER mutations in 25% to 30% of patients, a greater understanding is needed of the underlying mechanisms causing resistance to hormone therapy.

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

HER2 mutations were discovered in 12 of 168 metastatic biopsies. Eight of these mutations were known to be activating. An assessment of available baseline biopsies showed that 4 out 5 patients with activating mutations had no evidence of HER2 baseline mutations, suggesting they emerged due to ER-directed treatment.

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

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

Nayar also reported that the laboratory findings translated to the clinic. She described a patient who was diagnosed in 2011 with stage 2 ER-positive, PR/HER2-negative breast cancer and 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. The patient then responded to the combination of fulvestrant and neratinib.

Regarding potential next 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.”

Commenting on the findings, moderator Elaine R. Mardis, PhD, co-executive director of the Institute for Genomic Medicine at Nationwide Children’s Hospital, said, “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.”

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

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

The 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). In patients with measurable disease, the ORR with the pertuzumab combination was 63.3% compared with 55.7% for trastuzumab and an AI alone.

A study recently published in The Lancet Oncology, suggests that the next step in this area might be not only dual targeting, but also trying to enhance the impact of endocrine therapy by adding a CDK4/6 inhibitor.

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

The study showed that the neoadjuvant combination of palbociclib (Ibrance), pertuzumab, fulvestrant, and trastuzumab had a high clinical response. Twenty-nine (97%) of 30 patients had a response, including 15 complete responses and 14 partial responses.

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.

The phase III ALTERNATIVE trial randomized 355 women 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). The 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; P = .0064). The median PFS was 8.3 months for the lapatinib/AI arm.