Palbociclib: A Review in HR-Positive,HER2-Negative,Advanced or Metastatic Breast Cancer

Oral palbociclib (Ibrance®) is a first-in-class, highly selective inhibitor of cyclin-dependent kinases 4 and 6 (i.e. a CDK4/6 inhibitor). It is indicated for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer, in combination with an aromatase inhibitor as initial endocrine-based therapy, and in combination with fulvestrant (with or without a luteinizing hormone-releasing hormone agonist) in those previously treated with endocrine therapy. In clinical trials, palbociclib in combination with letrozole as initial endocrine-based therapy in postmenopausal women (PALOMA-1 and PALOMA-2), or in combination with fulvestrant in pre-, peri-, or postmenopausal women with disease progression after endocrine therapy (PALOMA-3), significantly prolonged progression-free survival (PFS) and improved clinical benefit response (CBR) rates. Neutropenia was the most commonly reported any-grade and grade ≥ 3 adverse event. It was infrequently associated with febrile neutropenia (<2%) and generally manageable with a palbociclib dose delay, interruption or reduction, without the routine use of growth factors, and without affecting efficacy. In conclusion, oral palbociclib combination therapy is a valuable emerging option for use in patients with HR-positive, HER2-negative advanced or metastatic breast cancer.

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Expanded-Access Study of Palbociclib in Combination With Letrozole for Treatment of Postmenopausal Women With Hormone Receptor–Positive,HER2-Negative Advanced Breast Cancer

Purpose

Palbociclib is a cyclin-dependent kinase (CDK) 4 and 6 inhibitor that was conditionally approved in the United States (February 2015) and Canada (March 2016) with letrozole as initial endocrine-based therapy for postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. A palbociclib expanded-access program (EAP) was initiated as an interim measure to provide drug access before commercial availability of drug.

Palbociclib plus letrozole as first-line treatment for ER-positive and HER2-negative advanced breast cancer in Chinese women: a phase 1 study

BackgroundPalbociclib, a cyclin-dependent kinase 4 and 6 inhibitor, is approved in many countries for the treatment of ER-positive and HER2-negative advanced breast cancer in combination with endocrine therapy. We aimed to evaluate the pharmacokinetics, safety, and efficacy of palbociclib combined with letrozole as first-line treatment for ER-positive and HER2-negative advanced breast cancer.MethodsThis is a phase 1, open-label, single-arm study in Chinese women with ER-positive and HER2-negative advanced breast cancer. From cycle 1 day 1, patients received letrozole 2·5 mg orally once daily continuously plus palbociclib 125 mg orally once daily for 3 weeks followed by 1 week off treatment. Blood samples for pharmacokinetic evaluation of palbociclib were collected up to 120 h after a single dose of palbociclib in a lead-in phase and after palbociclib dose on cycle 1 day 21 for multiple dose pharmacokinetic evaluation. Predose blood samples for pharmacokinetic evaluation of palbociclib and letrozole were collected on days 19–21 of cycle 1 and cycle 2 day 1 (letrozole only). Disease assessments were done every 12 weeks from cycle 1 day 1. Safety was assessed per Common Terminology Criteria for Adverse Events, version 4.0. This study is registered with ClinicalTrials, number NCT02499146, and is ongoing but not recruiting.FindingsAs of March 16, 2016, the cutoff date, the study completed enrolment with 26 patients. All patients completed single dose pharmacokinetic evaluation and 13 completed multiple dose pharmacokinetic evaluation. After multiple doses, the steady-state palbociclib geometric mean area under the concentration–time curve from 0 to 24 h was 2005 ng × h/mL and maximum observed concentration was 112·3 ng/mL, similar to those obtained in Caucasian patients following the same dosing regimen. Comparisons of single dose and multiple dose pharmacokinetic data indicated linear pharmacokinetics of palbociclib. The geometric mean accumulation ratio of palbociclib exposure after multiple dose compared with single dose was 2·1, consistent with a terminal half-life of 23·4–27·5 h. Trough concentrations of letrozole were similar to concentrations obtained in Caucasian patients. No deaths or permanent discontinuations due to adverse events were reported. One serious adverse event occurred but was not considered to be treatment-related. The most common clustered adverse events were neutropaenia (n=20, 77%), leukopaenia (n=19, 73%), and anemia (n=11, 42%), with neutropaenia (n=15, 58%) and leukopaenia (n=8, 31%) the most common grade 3–4 adverse events.InterpretationNo dose adjustment for palbociclib is needed based on the Chinese population. The toxicity of palbociclib in combination with letrozole treatment was tolerable and manageable.FundingPfizer Inc.     

Systemic therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative early stage and metastatic breast cancer

Hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is defined by the presence of the estrogen receptor and/or the progesterone receptor and the absence of HER2 gene amplification. HR-positive/HER2-negative breast cancer accounts for 65%–70% of all breast cancers, and incidence increases with increasing age. Treatment varies by stage, and endocrine therapy is the mainstay of treatment in both early stage and late-stage disease. Combinations with cyclin-dependent kinase 4/6 inhibitors have reduced distant recurrence in the early stage setting and improved overall survival in the metastatic setting. Chemotherapy is used based on stage and tumor biology in the early stage setting and after endocrine resistance for advanced disease. New therapies, including novel endocrine agents and antibody-drug conjugates, are now changing the treatment landscape. With the availability of new treatment options, it is important to define the optimal sequence of treatment to maximize clinical benefit while minimizing toxicity. In this review, the authors first discuss the pathologic and molecular features of HR-positive/HER2-negative breast cancer and mechanisms of endocrine resistance. Then, they discuss current and emerging therapies for both early stage and metastatic HR-positive/HER2-negative breast cancer, including treatment algorithms based on current data.     

Palbociclib enhances activin‐SMAD‐induced cytostasis in estrogen receptor‐positive breast cancer

Cyclin‐dependent kinase (CDK) 4 and CDK6 inhibitors are effective therapeutic options for hormone receptor (HR)‐positive, human epidermal growth factor receptor 2 (HER2)‐negative advanced breast cancer. Although CDK4/6 inhibitors mainly target the cyclin D‐CDK4/6‐retinoblastoma tumor suppressor protein (RB) axis, little is known about the clinical impact of inhibiting phosphorylation of other CDK4/6 target proteins. Here, we focused on other CDK4/6 targets, SMAD proteins. We showed that a CDK4/6 inhibitor palbociclib and activin‐SMAD2 signaling cooperatively inhibited cell cycle progression of a luminal‐type breast cancer cell line T47D. Palbociclib enhanced SMAD2 binding to the genome by inhibiting CDK4/6‐mediated linker phosphorylation of the SMAD2 protein. We also showed that cyclin G2 plays essential roles in SMAD2‐dependent cytostatic response. Moreover, comparison of the SMAD2 ChIP‐seq data of T47D cells with those of Hs578T (triple‐negative breast cancer cells) indicated that palbociclib augmented different SMAD2‐mediated functions based on cell type, and enhanced SMAD2 binding to the target regions on the genome without affecting its binding pattern. In summary, palbociclib enhances the cytostatic effects of the activin‐SMAD2 signaling pathway, whereas it possibly strengthens the tumor‐promoting aspect in aggressive breast cancer.     

Progression-Free Survival for Real-World Use of Palbociclib in Hormone Receptor-Positive Metastatic Breast Cancer

BackgroundAdditional use of cyclin-dependent kinase 4/6 inhibitors with endocrine therapy improves progression-free survival (PFS) in advanced hormone receptor (HR)-positive HER2-negative breast cancer. However, neutropenia is a common reason for dose reductions, leading to concerns about palbociclib efficacy at lower doses. A safety analysis confirmed no PFS differences between palbociclib doses in the second-line setting, but to our knowledge, this has not been evaluated for first-line treatment.Patients and MethodsIn this retrospective, single-center cohort study we evaluated real-world use of first-line palbociclib with aromatase inhibitor (AI) treatment in HR-positive, HER2-negative metastatic breast cancer patients who received treatment between February 2015 and July 2017. The primary objective was to determine PFS of treatment with palbociclib and an AI in a real-world first-line setting. Secondary objectives included determining the PFS for patients treated with palbociclib on the basis of final doses, time to first dose reduction, time to treatment failure (TTF), and safety.ResultsSeventy patients were included in the final analysis. Median PFS was 26.4 months. No significant differences in PFS were observed on the basis of final doses of palbociclib (P = .77). Time to first dose reduction was 2.3 months. Median TTF was 26.1 months. Dose delays, reductions, and Grade 3/4 neutropenia were common (63%, n = 44; 57%, n = 40; and 62%, n = 43, respectively).ConclusionReal-world first-line palbociclib treatment produced outcomes similar to those in PALOMA-2 (Palbociclib and Letrozole in Advanced Breast Cancer) (median PFS 26.4 months vs. 24.8 months) despite more dose reductions (57%, n = 40 vs. 36%, n = 160) and shorter time to first dose reduction (2.3 vs. 3.0 months). No significant differences in PFS were observed for the varying palbociclib doses. Palbociclib dose reductions might not significantly affect PFS in the first-line setting.     

Cyclin-dependent kinase 4/6 inhibitors in hormone receptor-positive early breast cancer: preliminary results and ongoing studies

The cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitors (CDK4/6i) induce cell cycle arrest in the G1 phase what eventually can prevent the proliferation of cancer cells. The CDK4/6i have changed the landscape of treatment options for ER-positive, HER2-negative metastatic breast cancer. Currently, palbociclib, ribociclib, and abemaciclib are approved by the US Food and Drug Administration in this setting. This success encouraged the researchers to examine CDK4/6i activity in (neo)adjuvant setting. In this review, clinical data to date and ongoing clinical trials with palbociclib, ribociclib, and abemaciclib in the early breast cancer are discussed. A literature search of these topics was carried out using PubMed and data reported at international oncology meetings and clinicaltrials.gov were included. Currently, we have the early promising data from Phase II clinical trials of CDK4/6i efficacy in the neoadjuvant setting in women with HR-positive breast cancer. Moreover, there are numerous studies that are in progress today in (neo)adjuvant setting.     

The Impact of Real-World Alternative Dosing Strategies of Palbociclib on Progression-Free Survival in Patients with Metastatic Breast Cancer

Background: Palbociclib, a cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitor, in combination with letrozole or fulvestrant has been demonstrated to prolong the progression-free survival (PFS) in patients with hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2-) metastatic breast cancer. In efforts to mitigate neutropenic toxicities, oncologists in real-world practice have prescribed alternative dosing strategies with palbociclib, yet the implication on PFS is unknown. Methods: We conducted a retrospective, observational chart review of all female patients at our clinics with HR+, HER2- metastatic breast cancer receiving palbociclib in combination with either letrozole or fulvestrant with a first dose initiated between June 2016 and December 2018 and followed their disease course until 30 April 2020. Results: The median PFS for all clinic patients receiving palbociclib and letrozole (n = 63) was 40.8 months (95% confidence interval (CI) 25.6–not estimable) and 16.97 months (95% CI 8.57–not estimable) for patients receiving palbociclib and fulvestrant (n = 11). We identified seven alternative dosing strategies prescribed by oncologists, the most prevalent being prescribing palbociclib for three weeks on and two weeks off (n = 8). The Kaplan–Meier curves for PFS in patients receiving letrozole and palbociclib prescribed alternative dosing strategies appear to diverge from monograph dosing early in the treatment. Many patients prescribed palbociclib using alternative dosing strategies continued to be observed even by the 18-month timepoint. The prevalence of grade 4 neutropenia was lower for patients on palbociclib with letrozole, suggesting a possible mitigation of severe neutropenia with alternative dosing strategies. Conclusions: We conclude that alternative dosing strategies used by oncologists such as prescribing palbociclib for three weeks on, two weeks off may achieve comparable disease control while mitigating neutropenic toxicities when compared to standard monograph dosing recommendations, prolonging treatment tolerability and adherence. Further large-scale studies are needed to confirm these results for future clinical adoption.     

PI3K inhibitors in trastuzumab-resistant HER2-positive breast cancer cells with PI3K pathway alterations

The activation of the PI3K signaling pathway resulting from genetic alterations induces carcinogenesis and resistance to anticancer therapies. Breast cancer is a major malignancy that is associated with dysregulation of the PI3K signaling pathway. PIK3CA mutations and PTEN loss occur in every subtype of breast cancer. PI3K inhibitors are being evaluated in breast cancer after the success of an alpha isoform-specific PI3K inhibitor in estrogen receptor (ER)-positive/HER2-negative metastatic breast cancer. Some preclinical data indicate the potential for PI3K/mTOR targeting in combination with trastuzumab for HER2-positive breast cancer with or without expression of the estrogen receptor. However, the role of this therapy in HER2-positive breast cancer with PIK3CA mutations and/or PTEN loss remains unclear. We examined three HER2-positive, ER-negative breast cancer cell lines to determine the efficacy of a novel alpha isoform-specific PI3K inhibitor in combination with trastuzumab. The results indicated that this combination was effective in PIK3CA-mutant or PTEN-deficient breast cancer cells by inducing apoptosis and inhibiting the expression of downstream proteins. PTEN loss by siRNA modulation in parental HER2-positive cancer cells with PI3K signaling pathway alterations could not confer resistance to alpelisib or GDC-0077 plus trastuzumab. We selected the CK-MB-1 cell line without alterations in the PI3K pathway to demonstrate that PI3K inhibitors plus trastuzumab represented a biomarker-specific treatment. In vivo effects of alpelisib plus trastuzumab were tested and confirmed in a mouse model, showing the combination strategy offered the best opportunity to achieve tumor volume reduction. With known safety profiles, this cytotoxic chemotherapy-free regimen warrants further attention as a biomarker-driven strategy for treating HER2-positive breast cancer.     

Palbociclib as single agent or in combination with the endocrine therapy received before disease progression for estrogen receptor-positive,HER2-negative metastatic breast cancer: TREnd trial

BackgroundThe activity of palbociclib as a single agent in advanced breast cancer has not been extensively studied, with the only available clinical data limited to heavily pretreated patients. Preclinical data suggests palbociclib may partially reverse endocrine resistance, though this hypothesis has not been evaluated in previous clinical studies. This phase II, open-label, multicenter study examined the activity of palbociclib monotherapy, as well as palbociclib given in combination with the same endocrine therapy (ET) that was received prior to disease progression, in postmenopausal women with moderately pretreated, estrogen receptor-positive, HER2 negative advanced breast cancer.Patients and methodsEligible women with advanced disease which had progressed on one or two prior ETs were randomized 1 : 1 to receive either palbociclib alone, or palbociclib in combination with the ET as previously received. Primary end point was clinical benefit rate (CBR); secondary end points included progression-free survival (PFS).ResultsBetween October 2012 and July 2016, a total of 115 patients were randomized. The CBR was 54% [95% confidence interval (CI): 41.5–63.7] for combination therapy, and 60% (95% CI: 47.8–72.9) for monotherapy. Median PFS was 10.8 months (95% CI: 5.6–12.7) for combination therapy, and 6.5 months (95% CI: 5.4–8.5) for monotherapy [hazard ratio (HR) 0.69; 95% CI: 0.4–1.1, exploratory P-value = 0.12]. Exploratory analyses revealed the PFS advantage for combination therapy was seen in the subgroup of patients who received prior ET for >6 months (HR 0.53; 95% CI: 0.3–0.9, exploratory P-value = 0.02), but not in those who received prior ET for ≤6 months.ConclusionPalbociclib has clinical activity as a single agent in women with moderately pretreated, oestrogen receptor-positive, HER2-negative advanced breast cancer. Palbociclib may have potential to reverse endocrine resistance in patients with a history of previous durable response to ET.Clinical trial informationNCT02549430     

Drug Insight: intracellular inhibitors of HER2--clinical development of lapatinib in breast cancer

Targeting the human epidermal growth factor receptor type 2 (HER2) in breast cancer patients whose tumors overexpress HER2 has been clearly demonstrated to be effective in clinical trials with the monoclonal antibody trastuzumab. Not all patients, however, respond to trastuzumab therapy. Lapatinib is an oral receptor tyrosine kinase inhibitor that targets HER2 and the EGFR. Preclinical data reveal that lapatinib has activity in trastuzumab-resistant cell lines as well as synergistic activity with trastuzumab. In a pivotal phase III trial, a combination of lapatinib and capecitabine significantly decreased the risk of disease progression relative to capecitabine alone in women with HER2-positive advanced or metastatic breast cancer previously treated with anthracyclines, taxanes, and trastuzumab. Other trials are evaluating lapatinib in inflammatory breast cancer--for which encouraging data have been reported--in combination with hormone therapy, in combination with trastuzumab, and as an adjunct to adjuvant therapy for early-stage disease. Notably, lapatinib has not been associated with serious or symptomatic cardiotoxicity in clinical trials. It can cross the blood-brain barrier and might therefore have a role in preventing central-nervous-system progression. These features make lapatinib an ideal agent to evaluate more fully in HER2-positive metastatic and early-stage breast cancer.     

A phase II feasibility study of palbociclib in combination with adjuvant endocrine therapy for hormone receptor-positive invasive breast carcinoma

BackgroundThe CDK4/6 inhibitor palbociclib prolongs progression-free survival in hormone receptor-positive/HER2-negative (HR+/HER2−) metastatic breast cancer when combined with endocrine therapy. This phase II trial was designed to determine the feasibility of adjuvant palbociclib and endocrine therapy for early breast cancer.Patients and methodsEligible patients with HR+/HER2− stage II–III breast cancer received 2 years of palbociclib at 125 mg daily, 3 weeks on/1 week off, with endocrine therapy. The primary end point was discontinuation from palbociclib due to toxicity, non-adherence, or events related to tolerability. A discontinuation rate of 48% or higher would indicate the treatment duration of 2 years was not feasible, and was evaluated under a binomial test using a one-sided α = 0.025.ResultsOverall, 162 patients initiated palbociclib; over half had stage III disease (52%) and most received prior chemotherapy (80%). A total of 102 patients (63%) completed 2 years of palbociclib; 50 patients discontinued early for protocol-related reasons (31%, 95% CI 24% to 39%, P = 0.001), and 10 discontinued due to protocol-unrelated reasons. The cumulative incidence of protocol-related discontinuation was 21% (95% CI 14% to 27%) at 12 months from start of treatment. Rates of palbociclib-related toxicity were congruent with the metastatic experience, and there were no cases of febrile neutropenia. Ninety-one patients (56%) required at least one dose reduction.ConclusionAdjuvant palbociclib is feasible in early breast cancer, with a high proportion of patients able to complete 2 years of therapy. The safety profile in the adjuvant setting mirrors that observed in metastatic disease, with approximately half of the patients requiring dose-modification. As extended duration adjuvant palbociclib appears feasible and tolerable for most patients, randomized phase III trials are evaluating clinical benefit in this population.Clinicaltrials.gov registrationNCT02040857.     

Real-World Treatment Patterns and Clinical Effectiveness of Palbociclib Plus an Aromatase Inhibitor as First-Line Therapy in Advanced/Metastatic Breast Cancer: Analysis from the US Syapse Learning Health Network

This retrospective single-arm study assessed real-world treatment patterns and clinical outcomes in patients with hormone receptor—positive/human epidermal growth factor receptor 2—negative (HR+/HER2−) advanced/metastatic breast cancer (A/MBC) who received palbociclib plus an aromatase inhibitor as first-line therapy in US community health systems. Using electronic health records from the Syapse Learning Health Network, 242 patients were identified as having received first-line palbociclib plus an aromatase inhibitor between 3 February 2015, and 31 July 2019 (data cutoff 1 February 2020) resulting in a minimum potential 6-month follow-up period. In total, 56.6% of patients had de novo A/MBC at initial breast cancer diagnosis, 50.8% had bone-only disease, and 32.2% had visceral disease. Median follow-up was 22.4 months. Disease progression (26.4%) and intolerance/toxicity (14.9%) were the main reasons for treatment discontinuation. The median (95% CI) real-world progression-free survival was 31.7 (27.9—not estimable (NE)) months and 2-year estimated overall survival (OS) rate was 78.0%. In total, 25.6% of patients died; however, OS data are limited by the small population size and insufficient follow-up time. These real-world effectiveness outcomes complement findings from other real-world studies and randomized controlled trials and support palbociclib plus an aromatase inhibitor as first-line therapy for HR+/HER2− A/MBC.     

Lidocaine enhances the efficacy of palbociclib in triple-negative breast cancer

The use of anesthetics in the surgical resection of tumors may influence the prognosis of cancer patients. Lidocaine, a local anesthetic, is known to act as a chemosensitizer and relieve pain in some cancers. In addition, palbociclib, a potent cyclin-dependent kinase (CDK) 4/6 inhibitor, has been approved for chemotherapy of advanced breast cancer. However, recent studies have revealed the acquired resistance of breast cancer cells to palbociclib. Therefore, the development of combination therapies that can extend the efficacy of palbociclib or delay resistance is crucial. This study investigated whether lidocaine would enhance the efficacy of palbociclib in breast cancer. Lidocaine synergistically suppressed the growth and proliferation of breast cancer cells by palbociclib. The combination treatment showed an increased cell cycle arrest in the G0/G1 phase by decreasing retinoblastoma protein (Rb) and E2F1 expression. In addition, it increased apoptosis by loss of mitochondrial membrane potential as observed by increases in cytochrome c release and inhibition of mitochondria-mediated protein expression. Additionally, it significantly reduced epithelial-mesenchymal transition and PI3K/AKT/GSK3β signaling. In orthotopic breast cancer models, this combination treatment significantly inhibited tumor growth and increased tumor cell apoptosis compared to those treated with a single drug. Taken together, this study demonstrates that the combination of palbociclib and lidocaine has a synergistic anti-cancer effect on breast cancer cells by the inhibition of the PI3K/AKT/GSK3β pathway, suggesting that this combination could potentially be an effective therapy for breast cancer.     

Does CDKN2A loss predict palbociclib benefit?

Palbociclib, an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6, was recently approved by the U.S. Food and Drug Administration in combination with letrozole for postmenopausal women with advanced hormone receptor–positive, her2-negative breast cancer. Patients with loss of CDKN2A (p16), an inherent negative regulator of cyclin-dependent kinases 4 and 6, were not separately studied because of the significant response of the patients selected based only on receptor status. Here, we report a patient with metastatic estrogen receptor– positive, her2-negative breast cancer with CDKN2A loss who experienced a clinical response to palbociclib.     

Trastuzumab Deruxtecan (DS-8201a): The Latest Research and Advances in Breast Cancer

The development of antibody–drug conjugates composed of a cytotoxic agent and a monoclonal antibody carrier offers an important alternative to classic chemotherapy strategies. Trastuzumab deruxtecan (DS-8201a) is a next-generation antibody–drug conjugate composed of a monoclonal anti-HER2 antibody and a topoisomerase I inhibitor, an exatecan derivative (DX-8951f). DS-8201a resulted in favorable outcomes in HER2-positive heavily pretreated breast cancer patients and also had a promising efficacy in patients with HER2-negative/low-expressing disease, whose options are limited. Interestingly, a recently published phase 2 trial (NCT03248492) reported 60% overall response and 97% disease control in patients with HER2-positive disease previously treated with multiple regimens, including trastuzumab emtansine. On the basis of recent clinical trials, the US Food and Drug Administration granted accelerated approval to DS-8201a in advanced or unresectable HER2-positive breast cancer pretreated with at least two HER2-targeting treatment lines. We review all preclinical and clinical data of DS-8201a regarding breast cancer.     

Palbociclib Plus Fulvestrant in Korean Patients from PALOMA-3 With Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer

In the PALOMA-3 trial, the median progression-free survival (PFS) was longer among patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) advanced breast cancer (ABC) treated with palbociclib plus fulvestrant than those treated with placebo plus fulvestrant. This subgroup analysis examined the efficacy and safety of palbociclib among Korean patients enrolled in PALOMA-3 (n = 43 [palbociclib group, n = 24; placebo group, n = 19]). In both groups, > 40% of patients were pre/perimenopausal at enrollment. The median PFS was significantly prolonged with palbociclib vs. placebo (12.3 [95% confidence interval (CI), 9.1–not estimable] vs. 5.4 months [95% CI, 1.9–9.2]; hazard ratio, 0.40 [95% CI, 0.19–0.83]; one-sided p = 0.005), and the confirmed objective response was 21.1% and 11.8%, respectively (odds ratio, 2.0 [95% CI, 0.24–24.8]). Neutropenia was the most common adverse event associated with palbociclib. Overall, palbociclib plus fulvestrant was effective and generally safe among Korean patients with HR+/HER2− ABC, regardless of menopausal status.     

Racial disparities in neutrophil counts among patients with metastatic breast cancer during treatment with CDK4/6 inhibitors

Breast Cancer Research and Treatment - The three CDK4/6 inhibitors (CDK4/6i) approved for use in HR-positive/HER2-negative metastatic breast cancer (MBC), palbociclib, ribociclib, and abemaciclib,...     

Everolimus Approved for HR-Positive Breast Cancer

The U.S. Food and Drug Administration approved the mTOR inhibitor everolimus (Afinitor; Novartis) for the treatment of postmenopausal women with advanced HR-positive, HER2-negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole.     

Antitumor and anticancer stem cell activity of a poly ADP-ribose polymerase inhibitor olaparib in breast cancer cells

Background

Although the poly adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitor olaparib is known to have potent antitumor activity in BRCA-related breast cancer cells, a limited number of preclinical and clinical studies have shown antitumor activity of olaparib in non-BRCA-related breast cancer. We investigated antitumor activity of olaparib in breast cancer cell lines derived from patients with nonfamilial sporadic breast cancer.

Methods

Effects of olaparib alone or in combination with five different chemotherapeutic agents on cell growth, cell cycle progression, apoptosis, and proportion of cancer stem cells using the mammosphere assay and CD44/CD24/ESA cell surface marker assay were investigated in a panel of six sporadic breast cancer cell lines. Extracellular-signal-regulated kinase (ERK) phosphorylation was also investigated to elucidate action mechanisms of olaparib.

Results

Olaparib inhibited the growth of two estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer cell lines and two ER-negative and HER2-negative breast cancer cell lines (50 % growth inhibitory concentrations 1.3–3.0 μM) associated with G2/M accumulation and induction of apoptosis. In contrast, two HER2-positive cell lines were resistant to olaparib. Interestingly, olaparib significantly decreased the proportion of putative cancer stem cells in either sensitive or resistant cell lines. In addition, olaparib increased expression of p-ERK. Combined treatments of olaparib with a mitogen-activated protein kinase kinase (MEK) inhibitor U0126 completely suppressed expression of p-ERK. These treatments also inhibited the G2/M accumulation and apoptosis induction by olaparib. Among five chemotherapeutic agents commonly used for breast cancer treatment, only an irinotecan metabolite SN38 showed additive antitumor activity with olaparib. Importantly, the combined treatment enhanced the increase in G2/M accumulation and apoptosis induction as well as a decrease in the proportion of cancer stem cells.

Conclusions

This study has indicated for the first time that the PARP inhibitor olaparib has substantial antitumor and anticancer stem cell activity in breast cancer cell lines of nonfamilial origin. Upregulation of p-ERK might explain, at least in part, antitumor and anticancer stem cell activity of olaparib. Combined treatment of olaparib with irinotecan might be effective in treatment of non-BRCA-related breast cancer.