Comparison of treatment-related adverse events of different Cyclin-dependent kinase 4/6 inhibitors in metastatic breast cancer: A network meta-analysis

BackgroundPalbociclib, ribociclib and abemaciclib have all been approved in combination with endocrine therapy in hormone-receptor positive, HER2 negative metastatic breast cancer. While the efficacy of these drugs appears similar, differences in safety and tolerability are apparent.MethodsWe searched PubMed and ASCO, ESMO and SABCS proceedings to identify randomized trials of palbociclib, ribociclib and abemaciclib. Data on common and serious adverse events (AE) were extracted for each approved drug. The odds ratio for each AE and the hazard ratio for progression-free survival were calculated relative to endocrine therapy alone. A network meta-analysis was then performed for each endocrine therapy backbone (aromatase inhibitor (AI) or fulvestrant) to compare ribociclib and abemaciclib to palbociclib.Results8 trials were included in the analysis and comprised 2799 patients receiving cyclin-dependent kinase 4/6 inhibitors palbociclib: 873 patients; ribociclib: 1153 patients; abemaciclib: 773 patients. In 5 trials (1524 patients), the endocrine therapy backbone was an AI and in 3 trials (1275 patients) it was fulvestrant. Compared to palbociclib, ribociclib and abemaciclib showed significantly lower grade 3–4 neutropenia, but significantly higher GI toxicity. Treatment discontinuation was higher with abemaciclib than other drugs. Efficacy of the 3 drugs was similar. Compared to palbociclib, for AI backbone, the HR for PFS for ribociclib was 0.98 and for abemaciclib 1.02. For fulvestrant backbone, the HR were 0.88 and 0.93 respectively.ConclusionsPalbociclib, ribociclib and abemaciclib have comparable efficacy, but differences in safety and tolerability. Abemaciclib has worse tolerability with significantly higher treatment discontinuation likely due to GI toxicity.     

Long-Term Pooled Safety Analysis of Palbociclib in Combination with Endocrine Therapy for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Updated Analysis with up to 5 Years of Follow-Up

BackgroundPrevious studies demonstrated the tolerability of palbociclib plus endocrine therapy (ET). This analysis evaluated safety based on more recent cutoff dates and a longer palbociclib treatment exposure.Patients and MethodsData were pooled from three randomized studies of patients with hormone receptor‐positive/human epidermal growth factor receptor 2‐negative (HR+/HER2−) advanced breast cancer (ABC), including postmenopausal women who had not received prior systemic treatment for advanced disease (PALOMA‐1/‐2) and pre‐ and postmenopausal women who had progressed on prior ET (PALOMA‐3).ResultsUpdated cutoff dates were December 21, 2017 (PALOMA‐1), May 31, 2017 (PALOMA‐2), and April 13, 2018 (PALOMA‐3). Total person‐years of treatment exposure were 1,421.6 with palbociclib plus ET (n = 872) and 528.4 with ET (n = 471). Any‐grade neutropenia and infections were more frequent with palbociclib plus ET (82.1% and 59.2%, respectively) than with ET (5.1% and 39.5%). The hazard ratios were 1.6 (p = .0995) for grade 3/4 infections, 1.8 (p = .4358) for grade 3/4 viral infections, 1.4 (p = .0001) for infections, and 30.8 (p < .0001) for neutropenia. Febrile neutropenia was reported in 1.4% of patients receiving palbociclib plus ET. Cumulative incidence of all‐grade hematologic adverse events in both arms peaked during the first year of treatment and plateaued over the 5 subsequent years. Interstitial lung disease was reported in 13 patients receiving palbociclib plus ET and 3 receiving ET.ConclusionThis 5‐year, long‐term analysis demonstrated that palbociclib plus ET has a consistent and stable safety profile and is a safe treatment for patients with HR+/HER2− ABC.Implications for PracticeSeveral treatments for patients with breast cancer are associated with long‐term or latent adverse events. This long‐term, 5‐year analysis demonstrated that palbociclib plus endocrine therapy has a consistent and stable safety profile without cumulative or delayed toxicities. These results further support palbociclib plus endocrine therapy as a safe and manageable treatment in clinical practice for patients with hormone receptor‐positive/human epidermal growth factor receptor 2‐negative advanced breast cancer.     

In real life,one-quarter of patients with hormone receptor-positive metastatic breast cancer receive chemotherapy as initial palliative therapy: a study of the Southeast Netherlands Breast Cancer Consortium

BackgroundThe objective of this study was to present initial systemic treatment choices and the outcome of hormone receptor-positive (HR+) metastatic breast cancer.Patients and methodsAll the 815 consecutive patients diagnosed with metastatic breast cancer in 2007–2009 in eight participating hospitals were identified. From the 611 patients with HR+ disease, a total of 520 patients with HER2-negative (HER2-) breast cancer were included. Initial palliative systemic treatment was registered. Progression-free survival (PFS) and overall survival (OS) per initial palliative systemic therapy were obtained using the Kaplan–Meier method and compared using the log-rank test.ResultsFrom the total of 520 patients with HR+/HER2- metastatic breast cancer, 482 patients (93%) received any palliative systemic therapy. Patients that received initial chemotherapy (n = 116) were significantly younger, had less comorbidity, had received more prior adjuvant systemic therapy and were less likely to have bone metastasis only compared with patients that received initial endocrine therapy (n = 366). Median PFS of initial palliative chemotherapy was 5.3 months [95% confidence interval (CI) 4.2–6.2] and of initial endocrine therapy 13.3 months (95% CI 11.3–15.5), with a median OS of 16.1 and 36.9 months, respectively. Initial chemotherapy was also associated with worse outcome in terms of PFS and OS after adjustment for prognostic factors.ConclusionsA high percentage of patients with HR+ disease received initial palliative chemotherapy, which was associated with worse outcome, even after adjustment of relevant prognostic factors.     

Patients sous palbociclib et hormonothérapie pour un cancer du sein métastatique : peut-on prédire la survenue d’une hématotoxicité précoce et sévère ?

IntroductionThe addition of palbociclib to endocrine therapy has been shown to improve progression free survival in hormone receptor positive metastatic breast cancer patients. This cyclin CDK4/6 inhibitor could expose patients to a grade 3–4 hematological toxicity, leading to treatment discontinuation or treatment interruption that is potentially associated with a lack of efficiency. The aim of this study was to identify predictive factors of severe early hematotoxicity (ESHT).MethodsThis retrospective cohort study included patients who started palbociclib in the Institut Sainte Catherine between December 1, 2016 and January 1, 2019 for the treatment of metastatic breast cancer. Individual data and hematological toxicity were collected from electronic medical records. ESHT was defined as the occurrence, during the first 3 cycles, of grade 4 or grade 3 hematological toxicity requiring palbociclib dose reduction.ResultsIn total, 181 patients (180 females) were included; median age was 67 years. Forty-six patients (25.4%) experienced an ESHT. Predictive factors of ESHT in multivariate analysis were a performance status (PS) of 2 or more (P = 0.024) and an history of radiotherapy of bone metastasis in the previous year (P = 0.003). Before palbociclib initiation, a neutrophil count below 3.37 g/L was predictive of ESHT with a sensibility of 76% and a specificity of 71%.ConclusionsECOG PS, bone radiotherapy within the year and low baseline neutrophils count are associated with ESHT in palbociclib-treated metastatic breast cancer patients. These elements could be useful for a careful monitoring leading to adapted therapy.     

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.     

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     

Randomized phase II study of lonaprisan as second-line therapy for progesterone receptor-positive breast cancer

BackgroundThe progesterone-receptor (PR) antagonists onapristone (type I) and mifepristone (type II) showed modest activity in hormone-receptor-positive breast cancer; however, onapristone in particular was associated with hepatotoxicity. Lonaprisan is a novel, type III PR antagonist that was well tolerated in phase I studies.Patients and methodsThis randomized, open-label, phase II study evaluated the efficacy and tolerability of lonaprisan as second-line endocrine therapy in postmenopausal women with stage IV, PR-positive, HER2-negative, metastatic breast cancer.ResultsPatients received once-daily lonaprisan 25 mg (n = 34) or 100 mg (n = 34). The primary objective was not met (≥35% clinical benefit rate: complete/partial responses at any time until month 6 or stable disease [SD] for ≥6 months from start of treatment). There were no complete/partial responses. In the 25 mg and 100 mg groups, 6 of 29 patients (21%) and 2 of 29 patients (7%), respectively, had SD ≥6 months. Overall, 61 of 68 patients (90%) had ≥1 adverse event (AE), the most frequent (≥10% overall) being fatigue, hot flush, dyspnoea, nausea, asthenia, headache, constipation, vomiting, and decreased appetite; 33 patients had serious AEs.ConclusionLonaprisan showed limited efficacy as second-line endocrine therapy in postmenopausal women with PR-positive metastatic breast cancer.     

Revisiting the definition of estrogen receptor positivity in HER2-negative primary breast cancer

BackgroundAlthough 1% has been used as cut-off for estrogen receptor (ER) positivity, several studies have reported that tumors with ER < 1% have characteristics similar to those with 1% ≤ ER < 10%. We hypothesized that in patients with human epidermal growth factor 2 (HER2)-negative breast cancer, a cut-off of 10% is more useful than one of 1% in discriminating for both a better pathological complete response (pCR) rate to neoadjuvant chemotherapy and a better long-term outcome with adjuvant hormonal therapy. Our objectives were to identify a percentage of ER expression below which pCR was likely and to determine whether this cut-off value can identify patients who would benefit from adjuvant hormonal therapy.Patients and methodsPatients with stage II or III HER2-negative primary breast cancer who received neoadjuvant chemotherapy followed by definitive surgery between June 1982 and June 2013 were included. Logistic regression models were used to assess the association between each variable and pCR. Cox models were used to analyze time to recurrence and overall survival. The recursive partitioning and regression trees method was used to calculate the cut-off value of ER expression.ResultsA total of 3055 patients were analyzed. Low percentage of ER was significantly associated with high pCR rate (OR = 0.99, 95% CI = 0.986–0.994,P<0.001). The recommended cut-off of ER expression below which pCR was likely was 9.5%. Among patients with ER ≥ 10% tumors, but not those with 1%≤ER < 10% tumors, adjuvant hormonal therapy was significantly associated with long time to recurrence (HR = 0.24, 95% CI = 0.16–0.36,P<0.001) and overall survival (HR = 0.32, 95% CI = 0.2–0.5,P<0.001).ConclusionStage II or III HER2-negative primary breast cancer with ER < 10% behaves clinically like triple-negative breast cancer in terms of pCR and survival outcomes and patients with such tumors may have a limited benefit from adjuvant hormonal therapy. It may be more clinically relevant to define triple-negative breast cancer as HER2-negative breast cancer with <10%, rather than <1%, of ER and/or progesterone receptor expression.     

Real-World Experience with CDK4/6 Inhibitors for Metastatic HR+/HER2− Breast Cancer at a Single Cancer Center

BackgroundA study was initiated at Roswell Park Comprehensive Cancer Center to capture the real-world experience related to the use of CDK4/6 inhibitors (Ciclibs) for the treatment of metastatic hormone receptor-positive and HER2-negative breast cancer (HR+/HER2-).Patients and MethodsA total of 222 patients were evaluated who received CDK4/6 inhibitors in the period from 2015 to 2021. Detailed clinical and demographic information was obtained on each patient and used to define clinical and demographic features associated with progression-free survival on CDK4/6 inhibitor-based therapies.ResultsIn this real-world analysis, the majority of patients received palbociclib as the CDK4/6 inhibitor with letrozole or fulvestrant as the predominant endocrine therapies. The median progression-free survival (PFS) in the letrozole (27.6 months) and fulvestrant (17.2 months) groups were comparable to that observed in clinical trials. As expected, age at start of the treatment and menopausal status influenced endocrine therapy utilization but were not associated with PFS. Patients with recurrent disease had shorter PFS (P = .0024) than those presenting with de novo metastasis. The presence of visceral metastasis trended toward shorter PFS (P = .051). Similarly, prior endocrine therapy (P = .003) or chemotherapy (P = .036) was associated with shorter PFS. Body mass index was not associated with PFS or with dose interruption and/or modification. While the number of minorities in this analysis is limited (n = 26), these patients as a group had statistically shorter PFS on treatment (P = .002).ConclusionsThe real-world progression-free survival with CDK4/6 inhibitors mimics that observed in the clinical trial. A number of clinical and demographic features were associated with PFS on CDK4/6 inhibitor-based therapy. Further studies are ongoing to validate these findings incorporating additional cancer centers.

This article reports a real-world experience related to the use of CDK4/6 inhibitors for the treatment of metastatic hormone receptor-positive and HER2-negative breast cancer, focusing on clinical and demographic features associated with progression-free survival.

Implications for PracticeThis study provides the real-world experience with the use of CDK4/6 inhibitors in the treatment of metastatic HR+/HER2− breast cancer. The work defines clinical and demographic features that impact the response to these agents and could offer guidance in preferred strategies for select manifestations of the disease. The study also suggests the need for more study of under-represented minority populations.     

Ribociclib for the treatment of hormone receptor-positive,human epidermal growth factor receptor 2-negative advanced breast cancer

Introduction: The emergence of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors marked a significant advancement in the treatment of advanced breast cancer. Ribociclib is an orally bioavailable, highly selective inhibitor of CDK4/6. In combination with various endocrine therapies, ribociclib has demonstrated clinical activity as a first-line therapy for patients with HR+, HER2? advanced breast cancer, without compromising the favorable toxicity profile associated with endocrine therapy. Thus, ribociclib is now considered a new standard of care for HR+, HER2? advanced breast cancer.

Areas covered: This review provides a concise overview of the preclinical and clinical development of ribociclib, including evidence of its clinical activity and safety profile when combined with endocrine therapy in HR+, HER2? advanced breast cancer.

Expert commentary: CDK4/6 inhibition represents a promising treatment option for patients with HR+ metastatic breast cancer. Ribociclib significantly improved progression-free survival in patients receiving first-line endocrine therapy for HR+, HER2? advanced breast cancer. Planned and ongoing trials investigating ribociclib in combination with other endocrine therapies and in various clinical settings will help to determine the optimal treatment sequence for different patient populations.     

Association between the HER2 Ile655Val polymorphism and response to trastuzumab in women with operable primary breast cancer

BackgroundHuman epidermal growth factor receptor 2 (HER2) Ile655Val polymorphism may affect the efficacy of trastuzumab treatment of breast cancer.Patients and methodsHER2 Ile655Val polymorphism was determined in 4167 patients with primary breast cancer using a polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) assay. We investigated the associations between the HER2 Ile655Val polymorphism and clinical outcomes in women with HER2-negative breast cancer and with HER2-positive breast cancer who received trastuzumab or who did not.ResultsAt a median follow-up of 44 months, HER2 Ile655Val polymorphism was not significantly associated with survival either in the entire study population of 4167 patients or in 2976 HER2-negative breast cancer patients. Among 816 HER2-positive patients who received adjuvant chemotherapy and/or endocrine therapy without trastuzumab treatment, patients with the Val/Ile or the Val/Val genotype had a significantly worse disease-free survival (DFS) and distant DFS (DDFS) than those with the Ile/Ile genotype (DFS, adjusted hazard ratio [HR] 1.5; 95% confidence interval [CI] 1.0–2.3; P = 0.037; DDFS, adjusted HR 1.9; 95% CI 1.2–2.9 P = 0.005). In contrast, among 212 HER2-positive patients who received chemotherapy in combination with trastuzumab treatment, patients with the Val/Ile or the Val/Val genotype had a significantly better DFS and DDFS than those with the Ile/Ile genotype (5-year DFS, 100% versus 83%; P = 0.008; 5-year DDFS, 100% versus 89%; P = 0.031).ConclusionsHER2 Ile655Val polymorphism affects the function of HER2 gene only restricted in HER2-positive breast cancers. HER2-positive breast cancer patients with the Val variant have an aggressive phenotype, but are sensitive to trastuzumab treatment.     

Observation versus late reintroduction of letrozole as adjuvant endocrine therapy for hormone receptor-positive breast cancer (ANZ0501 LATER): an open-label randomised,controlled trial

BackgroundDespite the effectiveness of adjuvant endocrine therapy in preventing breast cancer recurrence, breast cancer events continue at a high rate for at least 10 years after completion of therapy.Patients and methodsThis randomised open label phase III trial recruited postmenopausal women from 29 Australian and New Zealand sites, with hormone receptor-positive early breast cancer, who had completed ≥4 years of endocrine therapy [aromatase inhibitor (AI), tamoxifen, ovarian suppression, or sequential combination] ≥1 year prior, to oral letrozole 2.5 mg daily for 5 years, or observation. Treatment allocation was by central computerised randomisation, stratified by institution, axillary node status and prior endocrine therapy. The primary outcome was invasive breast cancer events (new invasive primary, local, regional or distant recurrence, or contralateral breast cancer), analysed by intention to treat. The secondary outcomes were disease-free survival (DFS), overall survival, and safety.ResultsBetween 16 May 2007 and 14 March 2012, 181 patients were randomised to letrozole and 179 to observation (median age 64.3 years). Endocrine therapy was completed at a median of 2.6 years before randomisation, and 47.5% had tumours of >2 cm and/or node positive. At 3.9 years median follow-up (interquartile range 3.1–4.8), 2 patients assigned letrozole (1.1%) and 17 patients assigned observation (9.5%) had experienced an invasive breast cancer event (difference 8.4%, 95% confidence interval 3.8% to 13.0%, log-rank test P = 0.0004). Twenty-four patients (13.4%) in the observation and 14 (7.7%) in the letrozole arm experienced a DFS event (log-rank P = 0.067). Adverse events linked to oestrogen depletion, but not serious adverse events, were more common with letrozole.ConclusionThese results should be considered exploratory, but lend weight to emerging data supporting longer duration endocrine therapy for hormone receptor-positive breast cancer, and offer insight into reintroduction of AI therapy.Clinical Trials NumberAustralian New Zealand Clinical Trials Registry (www.anzctr.org.au), ACTRN12607000137493     

Stability of HER2-positive status in breast carcinoma: a comparison between primary and paired metastatic tumors with regard to the possible impact of intervening trastuzumab treatment

BackgroundTo date, the stability of human epidermal growth factor receptor 2 (HER2)-positive primary breast carcinomas during disease progression and the role of intervening trastuzumab treatment in the loss of HER2-positive status in paired metastases remain under-investigated.Materials and methodsSixty-six patients with HER2-positive primary carcinoma and paired metastasis were evaluated. We examined the overall agreement of the HER2 status and compared the status agreement between 38 trastuzumab-treated patients and 28 trastuzumab-naive control patients. The impact of chemotherapy, endocrine therapy, metastatic site (locoregional or distant), and time to relapse (≥5 or <5 years) on the HER2 status change was assessed.ResultsFifty-six (84.9%) patients had HER2 status agreement between paired tumors; 10 patients had HER2-positive-to-negative conversion. The agreement rate in the trastuzumab-treated group and in the control group was comparable (86.8% versus 82.1%) (P = 0.858). Chemotherapy, endocrine therapy, metastatic site, and time to relapse did not significantly affect HER2 stability in either group. In the discordant tumor pairs, variations in testing methods and borderline scores were common.ConclusionsHER2-positive status remained unchanged in most paired metastases. Loss of HER2-positive status did not seem to be affected by trastuzumab treatment. Differences in testing and interpretation may account for the discordance in some cases.     

Palbociclib or Ribociclib in First-Line Treatment in Patients With Hormone Receptor–Positive/Human Epidermal Receptor 2–Negative Advanced or Metastatic Breast Cancer? A Perspective Based on Pharmacologic Costs

PurposeTo assess the pharmacologic costs of CDK4/6 inhibitors (palbociclib and ribociclib) in hormone receptor–positive (HR⁺)/human epidermal receptor 2–negative (HER2^?) advanced or metastatic breast cancer (BC). Pivotal phase 3 randomized controlled trials (RCTs) were considered.DiscussionTwo phase 3 RCTs including 1334 patients were considered. European Society for Medical Oncology Magnitude of Clinical Benefit Scale reached grade 3 for the PALOMA-2 and MONALEESA-2 trials. Pharmacologic costs of palbociclib and ribociclib at full dose were similar, at €3864 and €4002 per month of progression-free survival (PFS) gained, respectively. The reduction of dose of ribociclib (36.1% in the pivotal RCT vs. 36.0% of palbociclib in pivotal RCT) resulted in €2718 and €1348 per month of PFS gained at 400 and 200 mg daily, respectively.ConclusionWhen pharmacologic costs of drugs are combined with the measure of efficacy represented by PFS, both palbociclib and ribociclib are cost-effective first-line treatments in postmenopausal women with HR⁺/HER2^? advanced or metastatic BC, with a lower cost in favor of ribociclib in patients with dose reduction.     

Concurrent and sequential initiation of ovarian function suppression with chemotherapy in premenopausal women with endocrine-responsive early breast cancer: an exploratory analysis of TEXT and SOFT

BackgroundRecent breast cancer treatment guidelines recommend that higher-risk premenopausal patients should receive ovarian function suppression (OFS) as part of adjuvant endocrine therapy. If chemotherapy is also given, it is uncertain whether to select concurrent or sequential OFS initiation.Design and methodsWe analyzed 1872 patients enrolled in the randomized phase III TEXT and SOFT trials who received adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer and upon randomization to an OFS-containing adjuvant endocrine therapy, initiated gonadotropin-releasing-hormone-agonist triptorelin. Breast cancer-free interval (BCFI) was compared between patients who received OFS concurrently with chemotherapy in TEXT (n = 1242) versus sequentially post-chemotherapy in SOFT (n = 630). Because timing of trial enrollment relative to adjuvant chemotherapy differed, we implemented landmark analysis re-defining BCFI beginning 1 year after final dose of chemotherapy (median, 15.5 and 8.1 months from enrollment to landmark in TEXT and SOFT, respectively). As a non-randomized treatment comparison, we implemented comparative-effectiveness propensity score methodology with weighted Cox modeling.ResultsDistributions of several clinico-pathologic characteristics differed between groups. Patients who were premenopausal post-chemotherapy in SOFT were younger on average. The median duration of adjuvant chemotherapy was 18 weeks in both groups. There were 231 (12%) BC events after post-landmark median follow-up of about 5 years. Concurrent use of triptorelin with chemotherapy was not associated with a significant difference in post-landmark BCFI compared with sequential triptorelin post-chemotherapy, either in the overall population (HR = 1.11, 95% CI 0.72–1.72; P = 0.72; 4-year BCFI 89% in both groups), or in the subgroup of 692 women <40 years at diagnosis (HR = 1.13, 95% CI 0.69–1.84) who are less likely to develop chemotherapy-induced amenorrhea.ConclusionBased on comparative-effectiveness modeling of TEXT and SOFT after about 5 years median follow-up, with limited statistical power especially for the subgroup <40 years, neither detrimental nor beneficial effect of concurrent administration of OFS with chemotherapy on the efficacy of adjuvant therapy that includes chemotherapy was detected.Clinicaltrials.govNCT00066690 and NCT00066703.     

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.     

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.

Oncologists' Recommendations for Adjuvant Therapy in Hormone Receptor—Positive Breast Cancer Patients of Varying Age and Health Status

BackgroundCurrently, evidence supports the use of adjuvant endocrine therapy with aromatase inhibitors in post-menopausal patients with hormone receptor (HR)—positive breast cancer. The goal of the current study is to understand the effect of patient age and health status on oncologists' decision to recommend adjuvant treatment (endocrine therapy and chemotherapy) in older women with HR-positive breast cancer.Patients and MethodsAn online survey was conducted, with questions related to a hypothetical patient of varying age and health status with a T2 N2 HR-positive, HER2-negative breast cancer. Treatment options included chemotherapy and endocrine therapy, endocrine therapy alone, or no therapy. Respondents (n = 151) were further asked to specify use of either tamoxifen or aromatase inhibitors. A generalized linear mixed-effects model was used to determine the effect of age and health status on recommendations.ResultsAs the hypothetical patient's age increased or health status deteriorated, oncologists (n = 151) were less likely to recommend a combination of chemotherapy and endocrine therapy (P < .0001 for both). In contrast, oncologists were more likely to recommend endocrine therapy alone with advanced age and deteriorating health status (P < .0001 for both). Oncologists were more likely to choose treatment with aromatase inhibitors as opposed to tamoxifen (P < .01), irrespective of age or health status.ConclusionWith increasing age and declining health status, oncologists were more likely to recommend endocrine therapy alone as opposed to chemotherapy with endocrine therapy. Oncologists were most likely to recommend aromatase inhibitors, irrespective of age or health status.