Adjuvant cyclin-dependent kinase 4/6 inhibition in hormone receptor-positive breast cancer: One Monarch to rule them all?

The use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors has dramatically improved outcomes for patients with metastatic, hormone receptor (HR)-positive breast cancer. Because of the continued high rate of relapse in patients with node-positive, HR-positive disease, evaluating these agents in the adjuvant setting is the logical next step. Three adjuvant CDK inhibitor trials have been reported to date, with only 1 of them showing a statistical advantage for the CDK inhibitor in comparison with endocrine therapy alone. These trials have key similarities and differences that could explain the disparate results. The one positive trial has a relatively short follow-up, and continued analysis is critical to confirm the benefit of adjuvant CDK inhibition in this setting. It is imperative that predictive biomarkers be determined so that these agents can be used in the patients most likely to benefit and thus the additional toxicity and expense can be avoided in those who do not require these agents. LAY SUMMARY: There is a critical need for new agents to prevent relapse in patients with hormone receptor-positive breast cancer. Trials to date evaluating cyclin-dependent kinase inhibitors, which decrease how quickly cancer cells multiply, have shown mixed results, with only 1 trial demonstrating that these agents decrease recurrence.

NCCN Guidelines® Insights: Breast Cancer, Version 4.2021.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer-focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor-positive, HER2-negative breast cancer.

Therapy after cyclin-dependent kinase inhibition in metastatic hormone receptor-positive breast cancer: Resistance mechanisms and novel treatment strategies.

Endocrine therapy has been the standard of care for patients with metastatic hormone receptor (HR)-positive, HER2-negative breast cancer since the 1970s, improving survival while avoiding the toxicities associated with cytotoxic chemotherapy. However, all HR-positive tumors ultimately develop resistance to endocrine therapy. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have more recently become an important component of the management of this breast cancer subtype, significantly delaying time to the disease progression and improving survival when combined with endocrine therapy. However, as with endocrine therapy alone, treatment resistance remains a universal phenomenon. As more women receive CDK4/6 inhibitors as part of their treatment, the management of de novo and acquired resistance to combined CDK4/CDK6 inhibitor plus endocrine therapy regimens has emerged as an important clinical challenge. Several resistance mechanisms have been described, including alterations in the CDK4/6/cyclin D complex or its major effector retinoblastoma protein (pRb), bypass signaling through other cyclin/CDK complexes and activation of upstream signaling pathways, in particular the PI3K/mTOR pathway, but robust biomarkers to predict resistance remain elusive, and the role for continuing CDK4/6 inhibitors after progression remains under investigation. Novel strategies being evaluated in clinical trials include the continuation of CDK4/6 inhibitors through progression, as well as triplet therapy combinations with PI3K inhibitors or immune checkpoint inhibitors.

Phase 1 study of TTC-352 in patients with metastatic breast cancer progressing on endocrine and CDK4/6 inhibitor therapy.

PURPOSE: TTC-352 is a selective human estrogen receptor (ER) partial agonist developed for treatment of hormone-refractory ER + breast cancer. METHODS: This was an accelerated dose escalation study with the primary endpoint of maximum tolerated dose that evaluated five dose levels of TTC-352 in breast cancer progressing after at least two lines of hormonal therapy including one in combination with a CDK4/6 inhibitor. The secondary objectives were to determine treatment tolerability, pharmacokinetics of TTC-352, best response, progression-free survival (PFS), and PKCα expression in tumors. RESULTS: The study enrolled 15 patients. No dose-limiting toxicity was observed. Patients experienced the following grade 3 toxicities: asymptomatic pulmonary embolism, diarrhea, aspartate transaminase elevation, and myalgia, and one grade 4 toxicity of gamma glutamyltransferase elevation. Pharmacokinetic half-life was 7.6-14.3 h. The intra- and inter-individual variability for AUC0-∞ hampered assessment of the relationship between dose and AUC0-∞. Median PFS was 58 days (95% CI = 28,112). Higher PKCα expression in tumor stroma was associated with a trend toward longer PFS. CONCLUSIONS: TTC-352 demonstrates safety and early clinical evidence of antitumor activity against heavily pretreated hormone-refractory breast cancer. Based upon TTC-352 plasma concentrations and tolerability, the 180 mg twice a day is recommended for further testing. (ClinicalTrials.gov Identifier: NCT03201913).

Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.

Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.

NCCN Guidelines Insights: Breast Cancer, Version 3.2018.

These NCCN Guidelines Insights highlight the updated recommendations for use of multigene assays to guide decisions on adjuvant systemic chemotherapy therapy for women with hormone receptor-positive, HER2-negative early-stage invasive breast cancer. This report summarizes these updates and discusses the rationale behind them.

Breast Cancer, Version 4.2017, NCCN Clinical Practice Guidelines in Oncology.

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.

Adjuvant Endocrine Therapy.

The use of hormonal therapy in breast cancer has improved the overall outcome for patients with early-stage hormone receptor-positive disease. The choice of hormone therapy is related to multiple factors, including menopausal state, patient preference, and potential side effects. Molecular profiling has allowed therapy to be tailored for an individual patient to some extent. However, further molecular studies are needed to individualize the choice and length of adjuvant hormone therapy. Ongoing studies are evaluating the role of additional targeted therapies, such as CDK4/6 inhibitors, to further improve outcome for patients with early-stage hormone receptor-positive breast cancer.

Phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer.

Introduction Suppressing both androgens and estrogens may circumvent hormone receptor resistance in breast cancer by reducing androgen receptor stimulation. Selective inhibition of the 17, 20-lyase enzyme by orteronel leads to decreased androgen production in men and would be anticipated to reduce estrogen and androgen production in women. Thus, we conducted a phase 1b study of orteronel in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer. Methods The primary objective was to identify the recommended phase 2 dose (R2PD) of orteronel in women; escalation was via standard 3 + 3 design. The initial dose was 300 mg BID and escalated to 400 mg BID. Cycle length was 28 days. Enrolled patients had HR+ metastatic breast cancer and were evaluated every 8 weeks for disease progression. Results Eight heavily pre-treated women enrolled [median age: 57 yo (range 47-73)]. Four received 300 mg BID at dose level 1; 4 received 400 mg BID at dose level 2. No dose limiting toxicities (DLTs) were observed. Adverse events (AE) at least possibly related to orteronel included grade 1-2 nausea (n = 4) and bone pain (n = 3), and grade 1 hypokalemia, hot flashes, myalgia and AST elevation (n = 2). The only grade 3 AE was hypertension (n = 2) with 8 patients receiving 34 cycles of treatment. No objective responses were seen; clinical benefit was seen in 2 patients with stable disease for more than 6 months. Serum estrogens and testosterone were suppressed from baseline on both doses of orteronel. Conclusions Orteronel 400 mg BID is well tolerated in postmenopausal women, and significantly suppresses serum estrogens and testosterone. Clinical benefit was seen among heavily pretreated postmenopausal women with HR+ metastatic breast cancer.

NCCN Guidelines Insights: Breast Cancer, Version 1.2017.

These NCCN Guidelines Insights highlight the important updates/changes to the surgical axillary staging, radiation therapy, and systemic therapy recommendations for hormone receptor-positive disease in the 1.2017 version of the NCCN Guidelines for Breast Cancer. This report summarizes these updates and discusses the rationale behind them. Updates on new drug approvals, not available at press time, can be found in the most recent version of these guidelines at NCCN.org.

Systemic therapy for early-stage HER2-positive breast cancers: time for a less-is-more approach?

Trastuzumab-based chemotherapy has dramatically improved outcomes for patients with all stages of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Additional HER2-directed agents that have recently been approved are also expected to improve outcomes. Patients with small, lymph node-negative, HER2-positive breast cancers who are treated with trastuzumab-based chemotherapy demonstrate especially favorable responses, with 5-year recurrence rates of <5%. In this review, recent data regarding response rates among patients with early-stage HER2-positive breast cancer treated with trastuzumab-based chemotherapy are discussed. This review supports future studies of the possible omission of chemotherapy in a subset of patients with HER2-positive cancers, specifically those that coexpress hormone receptors.

Optimizing Endocrine Therapy for Breast Cancer.

Endocrine therapy has significantly improved outcomes for patients with early- and advanced-stage hormone-receptor (HR)-positive breast cancer. Despite the success of adjuvant endocrine therapy, some patients with early-stage disease will experience relapse. Additionally, all patients with advanced disease will eventually experience disease progression on endocrine therapy due to resistance. Improved understanding of the mechanisms associated with resistance to endocrine agents has recently led to the approval of new therapeutics. Multiple questions remain unanswered, including the optimal duration of adjuvant therapy, the role of ovarian ablation in early-stage breast cancer in premenopausal women, and how to best incorporate targeted agents with endocrine therapy in the metastatic setting. This article reviews the optimization of endocrine therapy in patients with HR-positive breast cancer, focusing on these controversial areas.

Proteomic identification of glycosylphosphatidylinositol anchor-dependent membrane proteins elevated in breast carcinoma.

The glycosylphosphatidylinositol (GPI) anchor is a lipid and glycan modification added to the C terminus of certain proteins in the endoplasmic reticulum by the activity of a multiple subunit enzyme complex known as the GPI transamidase (GPIT). Several subunits of GPIT have increased expression levels in breast carcinoma. In an effort to identify GPI-anchored proteins and understand the possible role of these proteins in breast cancer progression, we employed a combination of strategies. First, alpha toxin from Clostridium septicum was used to capture GPI-anchored proteins from human breast cancer tissues, cells, and serum for proteomic analysis. We also expressed short interfering RNAs targeting the expression of the GPAA1 and PIGT subunits of GPIT in breast cancer cell lines to identify proteins in which membrane localization is dependent on GPI anchor addition. Comparative membrane proteomics using nano-ESI-RPLC-MS/MS led to the discovery of several new potential diagnostic and therapeutic targets for breast cancer. Furthermore, we provide evidence that increased levels of GPI anchor addition in malignant breast epithelial cells promotes the dedifferentiation of malignant breast epithelial cells in part by increasing the levels of cell surface markers associated with mesenchymal stem cells.

A phase 2 study of everolimus combined with trastuzumab and paclitaxel in patients with HER2-overexpressing advanced breast cancer that progressed during prior trastuzumab and taxane therapy.

Increased activation of the PI3K/Akt/mTOR pathway is a common factor in putative mechanisms of trastuzumab resistance, resulting in dysregulation of cell migration, growth, proliferation, and survival. Data from preclinical and phase 1/2 clinical studies suggest that adding everolimus (an oral mTOR inhibitor) to trastuzumab plus chemotherapy may enhance the efficacy of, and restore sensitivity to, trastuzumab-based therapy. In this phase 2 multicenter study, adult patients with HER2-positive advanced breast cancer resistant to trastuzumab and pretreated with a taxane received everolimus 10 mg/day in combination with paclitaxel (80 mg/m(2) days 1, 8, and 15 every 4 weeks) and trastuzumab (4 mg/kg loading dose followed by 2 mg/kg weekly), administered in 28-day cycles. Endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients were enrolled; one remained on study treatment at the time of data cutoff. The median number of prior chemotherapy lines for advanced disease was 3.5 (range 1-11). The ORR was 21.8 %, the clinical benefit rate was 36.4 %, the median PFS estimate was 5.5 months (95 % confidence interval [CI]: 4.99-7.69 months), and the median OS estimate was 18.1 months (95 % CI: 12.85-24.11 months). Hematologic grade 3/4 adverse events (AEs) included neutropenia (25.5 % grade 3, 3.6 % grade 4), anemia (7.3 % grade 3), and thrombocytopenia (5.5 % grade 3, 1.8 % grade 4). Nonhematologic grade 3/4 AEs included stomatitis (20.0 %), diarrhea (5.5 %), vomiting (5.5 %), fatigue (5.5 %), and pneumonia (5.5 %), all grade 3. These findings suggest that the combination of everolimus plus trastuzumab and paclitaxel is feasible, with promising activity in patients with highly resistant HER2-positive advanced breast cancer. This combination is currently under investigation in the BOLERO-1 phase 3 trial.