For breast cancer that is estrogen receptor–positive, CDK4/6 inhibitors, given with endocrine therapy, have become the standard of care, especially in metastatic disease. However, resistance to both endocrine therapies and CDK4/6 inhibitors is common, and new approaches are needed to counteract this problem. Two novel approaches showing promise in early-phase trials were described by Carlos L. Arteaga, MD, who delivered the Giants of Cancer Care Lecture at the 2024 Miami Breast Cancer Conference.1
“One of these approaches pertains to the discovery of the therapeutic vulnerability in estrogen receptor–positive tumors that are RB [retinoblastoma] protein–deficient…, and the other pertains to HER2-activating mutations and their resistance to antiestrogens,” he said. Dr. Arteaga is Director of the Harold K. Simmons Comprehensive Cancer Center, Associate Dean of Oncology Programs at UT Southwestern Medical Center, and the Annette Simmons Distinguished University Chair in Breast Cancer Research.
Inhibiting PRMT5
CDK4/6 inhibitors require the RB protein to exert their antitumor effect. “They work by inhibiting the phosphorylation of RB, which upon dephosphorylation becomes activated,” Dr. Arteaga explained. This ultimately prevents transcription of molecules involved in cell cycle and cancer cell growth. “In the absence of RB, CDK4/6 inhibitors cannot work. About 10% of patients who experience disease progression on CDK4/6 inhibitors lose RB, and there is currently no targeted therapy for these patients. With widespread use of CDK4/6 inhibitors, this type of drug resistant tumors is likely to increase,” he added.
“About 10% of patients who experience disease progression on CDK4/6 inhibitors lose RB, and there is currently no targeted therapy for these patients. With widespread use of CDK4/6 inhibitors, this type of drug-resistant tumors is likely to increase.”— Carlos L. Arteaga, MD
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The loss of RB in the setting of CDK4/6 inhibition can be harnessed to combat resistance. Using CRISPR screening of RB1-knockout cells, Dr. Arteaga and his team identified protein arginine methyltransferase 5 (PRMT5), an enzyme involved in several cellular functions, as an essential gene in RB-deficient tumors. Genetic silencing of PRMT5 completely arrested growth of estrogen receptor–positive/RB1-knockout cells. Similar results were observed with PRMT5 inhibitors in clinical development. These compounds are probably used most effectively in combination with antiestrogens, he suggested.
The PRMT5 inhibitor pemrametostat suppressed levels of the biomarker symmetric dimethylarginine (SDMA) and inhibited estrogen receptor–positive/RB1-knockout cell viability. Pemrametostat also inhibited growth in dose-dependent fashion of an RB-deficient cell line xenograft and a drug-resistant organoid from a patient who experienced disease progression on the CDK4/6 inhibitor palbociclib. Synergistic activity—eg, statistically greater efficacy of the combination vs the single agent—was shown when pemrametostat was combined with fulvestrant, according to Dr. Arteaga.
“Pemrametostat inhibited SDMA levels and fulvestrant inhibited [estrogen receptor] expression in experimental breast tumors. Both drugs in combination inhibited both targets at the same time, potentially explaining their synergistic effect,” he added.
Agents in Development
Several nonselective PRMT5 inhibitors are in development. Phase I and II studies—PRT543, JNJ-64619178, PRT811, and SCR-6920—are underway or have been completed in solid tumors and some hematologic malignancies for pemrametostat. However, not all the findings have been positive, Dr. Arteaga acknowledged. Of note, these trials have not focused on enrolling patients with RB-deficient tumors.
HER2 Mutations and Resistance to Endocrine Therapies
A second mechanism of endocrine resistance and early escape from the effect of CDK4/6 inhibitors centers on activating mutations in the HER2 gene. HER2 mutations, which are seen in the absence of HER2 overexpression, occur in up to 8% of advanced estrogen receptor–positive breast cancers—less in primary disease and more in the invasive lobular subtype, Dr. Arteaga stated. They do not overlap with other alterations associated with endocrine resistance, such as loss of RB1, mutations in NF1 and KRAS, or FGFR1 amplification, but they occur concomitantly with mutations in TP53, PIK3CA, ERBB3, and CDH1.
“Most of the HER2 mutations are in estrogen receptor–positive tumors, and they happen in the absence of HER2 amplification. I want to emphasize that these tumors are clinically HER2-negative,” he said.
In the laboratory, estrogen receptor–positive breast cancer cells do not respond to estrogen suppression or to fulvestrant. “It’s becoming clear that HER2-mutant tumors have to be treated with both an antiestrogen and anti-HER2 therapy, specifically a HER2 tyrosine kinase inhibitor,” Dr. Arteaga said.
There are supportive data for this combination approach, as shown clinically with the irreversible pan-HER2 tyrosine kinase inhibitor neratinib and fulvestrant. Patients with advanced estrogen receptor–positive, HER2-mutated breast cancer treated with this doublet have achieved a longer progression-free survival than those treated with neratinib alone.2 Despite the benefit seen with this combination, acquired secondary HER2 mutations do emerge, and they appear to be casually associated with acquired resistance to neratinib.
“Unlike HER2/HER3 mutants (which mainly induce PI3K/AKT), HER2 double mutants (that is a primary and a secondary drug-resistant mutation) hyperactivate both PI3K/AKT and MEK/ERK pathways,” he said. Tumors with HER2 double mutants have also shown reduced sensitivity to the majority of HER2-targeted tyrosine kinase inhibitors but are sensitive to combined inhibition with HER2 and MEK.
“It’s becoming clear that HER2-mutant tumors have to be treated both with an antiestrogen and anti-HER2 therapy, specifically a HER2-targeted tyrosine kinase inhibitor.”— Carlos L. Arteaga, MD
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Investigators have also hypothesized that adding trastuzumab to treatment with fulvestrant and neratinib may be beneficial for patients with HER2-mutant advanced breast cancer. This potential benefit is reflected in the latest version of the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Both doublet and triplet regimens of fulvestrant plus neratinib, with or without trastuzumab, respectively, are category 2B recommendations for patients with advanced estrogen receptor–positive, HER2-mutant breast cancer that progresses on CDK4/6 inhibitors.
Future neoadjuvant trials will explore the combination of neratinib and letrozole in patients with newly diagnosed, operable HER2-mutant, estrogen receptor–positive invasive lobular breast cancer. The aim here is to boost pathologic complete response rates, which are typically very low for this subtype with endocine therapy and/or chemotherapy. Since these drugs are already available, the hope is to “treat the disease early, while still operable and potentially curable, thus aiming to meaningfully impact patient outcomes without disrupting current standards of care,” Dr. Arteaga commented.
DISCLOSURE: Dr. Arteaga has served as a consultant to Novartis, Eli Lilly, Merck, AstraZeneca, Daiichi Sankyo, OrigiMed, Taiho Oncology, Puma Biotechnology, Sanofi, Arvinas, Laekna Therapeutics, and Susan G. Komen Foundation.
REFERENCES
1. Arteaga C: Resistance to CDK4/6 inhibitors in ER+ breast cancer. 2024 Miami Breast Cancer Symposium. Giants of Cancer Care Lecture. Presented March 8, 2024.
2. Jhaveri K, Eli LD, Wildiers H, et al: Neratinib + fulvestrant + trastuzumab for HR-positive, HER2-negative, HER2-mutant metastatic breast cancer: Outcomes and biomarker analysis from the SUMMIT trial. Ann Oncol 34:885-898, 2023.
