Combination Approaches Combat Resistance to Endocrine Therapy in HR+ Breast Cancer

Virginia Powers, PhD
Published: Thursday, Mar 16, 2017

Ian E. Krop, MD, PhD

Ian E. Krop, MD, PhD

Genomic studies have made significant advancements in discovering methods to combat resistance to endocrine therapy in patients with hormone receptor (HR)–positive breast cancer over the past few years, according to Ian E. Krop, MD, PhD. Of particular interest are combination therapies blocking multiple driver pathways and resistance mechanisms.

“Extended aromatase inhibitor therapy will not solve the problem of late recurrence in HR-positive breast cancer, which remains the leading cause of breast cancer mortality, due largely to innate and acquired resistance to endocrine therapy,” noted Krop, chief and clinical research director of the Breast Oncology Center at Dana-Farber Cancer Institute, and assistant professor of medicine at Harvard Medical School, during a presentation at the 15th St. Gallen International Breast Cancer Conference. “Despite resistance to endocrine therapy, the integrity of the estrogen receptor [ER] is still maintained in most cases, leaving many cancers hormone dependent; however, what isn’t understood is tumor dormancy.”

Fundamentally, estradiol binding of the ER drives the transcription of targets like cyclin D1 and cell proliferation, he explained, “but there are multiple oncogenic drivers and resistance pathways in this subtype of breast cancer and combined blockade of both driver pathways and resistance mechanisms is fundamental and, in some cases, can be synergistic.”

Over 11 genomic alterations have been identified in primary and metastatic ER-positive tumors, with some mutations, such as ESR1, that lock the ER into the active conformation, resulting in constitutive ER activity.1 In vitro evidence has shown that ESR1 mutations are linked to resistance to hormonal therapy. This was confirmed by the BOLERO-2 trial of exemestane (Aromasin) with and without everolimus (Afinitor), which demonstrated that decreased overall survival (OS) was associated with the presence of an ESR1 mutation.2

In the BOLERO-2, SOFeA,3 PALOMA-3,4 and FERGI trials,5 the frequency of circulating tumor DNA ESR1 mutations in patients with ER-positive metastatic breast cancer was 28.8%, 39.1%, 25.3%, and 37%, respectively.

Preliminary data suggest that agents that degrade ER function, such as fulvestrant (Faslodex) or oral selective estrogen receptor degraders (SERDs), may overcome this mechanism of resistance.

The SOFeA trial showed that the presence of an ESR1 mutation was associated with worse outcome in patients treated with exemestane but not those receiving fulvestrant (HR, 0.52; 95% CI, 0.30-0.92; P = .02).3  Preliminary analysis of data from a phase I/II study in postmenopausal women with advanced HR+ breast cancer showed a clinical benefit in 38% of patients, including an objective response in 2 of 9 patients with ESR1 mutations following treatment with GDC-0810, a novel SERD.6 Krop noted that phase I studies of other SERDs, including AZD9496, bazedoxifene, RAD-1901, GDC-0927, and LCZ102 are underway, while GDC-0810 has proceeded to a phase II trial (NCT02569801).

According to Krop, somatic activating mutations in the gene encoding HER2 (ERBB2) occur in approximately 2% of breast cancers and are predominately clustered in the kinase domain. HER2 L755S AND V777L mutations confer estrogen-independent cell growth and resistance to endocrine therapy.

In vitro data suggest that neratinib, a potent HER2-kinase inhibitor, may act synergistically with fulvestrant to overcome resistance in HER2-mutant cancers. The combination showed comparable response rates to wild-type HER2 in cancer cells as with HER2 G309A, L755S, and V777L mutations.7 A preliminary analysis of data from the phase II SUMMIT trial demonstrated a best response rate of 33.3% with neratinib monotherapy compared to 54.5% with combined neratinib and fulvestrant in patients with ERBB2 mutant, HER2 non-amplified ER-positive metastatic breast cancer.8

Krop also discussed mutations in the PI3K/mTOR pathway as oncogenic drivers of HR-positive cancers, which may explain the clinical synergy seen with the combination of the mTOR inhibitor, everolimus, and hormonal agents. Evidence of crosstalk between the ER and PI3K/mTOR pathways resulting in ER activation by mTOR1 has been reported. Estradiol is also known to suppress apoptosis induced by blockade of PI3K/mTOR, and hyperactivation of this pathway has been observed in endocrine-resistant breast cancer cells. In a series of 547 human ER-positive breast cancer samples, the incidence of mutations in PI3K was 23% and 3% in PTEN.

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