bims-cyhorp 2022-10-09 papers

Issue of 2022–10–09
eight papers selected by
Piotr Okupski,

Biol Pharm Bull. 2022 ;45(10): 1476-1481

The Cyclin-Dependent Kinase 4/6 Inhibitor Abemaciclib Is Tolerated Better than Palbociclib by Advanced Breast Cancer Patients with High Serum Albumin Levels.

Hitomi Nakatsukasa, Masaya Takahashi, Katsuyuki Takahashi, Tsutomu Takashima, Yuka Asano, Tamami Morisaki, Shinichiro Kashiwagi, Satoru Noda, Yasutaka Nakamura.

The cyclin-dependent kinase (CDK) 4/6 inhibitors, palbociclib and abemaciclib, have been approved in Japan. However, the selection criteria for these drugs have not been established. Hence, we aimed to identify the risk factors for CDK4/6 inhibitor-induced intolerable adverse events requiring dose reduction or therapy cessation and to establish useful markers for choosing the appropriate CDK4/6 inhibitor, based on the incidence of the intolerable adverse events. This retrospective cohort analysis included patients with advanced breast cancer who received 125 mg/d palbociclib or 300 mg/d abemaciclib. We defined significant adverse events (SAEs) as side effects requiring dose reduction or therapy cessation. Thirty-six percent of the patients who received palbociclib (9/25) and 27.3% of those who received abemaciclib (9/33) experienced SAEs. In palbociclib and abemaciclib groups, baseline white blood cell (WBC) counts and serum albumin (ALB) levels, respectively, were significantly lower in patients who experienced SAEs than in those who did not (palbociclib: p = 0.007; abemaciclib: p = 0.004). According to the receiver operating characteristic curve analysis, the optimal cutoff values for baseline WBC count and ALB level were 5700/µL and 4.0 g/dL, respectively. Among patients with ALB levels >4.0 g/dL, the incidence of abemaciclib-induced SAEs was significantly lower than that of the palbociclib-induced SAEs (1/17 (5.9%) vs. 6/14 (42.9%), odds ratio: 11.0, 95% confidence interval: 1.07-583, p = 0.0281). Thus, a baseline WBC count ≤5700/µL and ALB level ≤4.0 g/dL may be risk factors for palbociclib and abemaciclib-induced SAEs, respectively. Also, high ALB levels can serve as a useful marker for choosing abemaciclib.

Keywords: abemaciclib; adverse effect; breast cancer; cyclin-dependent kinase (CDK) 4/6 inhibitor; palbociclib; serum albumin

DOI: https://doi.org/10.1248/bpb.b22-00338

Ecancermedicalscience. 2022 ;16 ed124

CDK 4/6 inhibitors for adjuvant therapy in early breast cancer-Do we have a clear winner?

Amol Akhade, Simon Van Wambeke, Bishal Gyawali.

CDK4/6 inhibitors have become the mainstay of treatment for patients with advanced hormone receptor positive and Human Epidermal Receptor -2 [ HER-2 ] negative breast cancer. Three CDK 4/6 inhibitor drugs are currently approved and available, including Palbociclib, Ribociclib and Abemaciclib. All three of these drugs have similar mechanism of action and other pharmacokinetic and pharmaco-dynamic properties and hold equivalent positions in cancer care guidelines. Surprisingly, however, in the adjuvant setting of early breast cancer, two trials of palbociclib have failed to show any benefit while abemaciclib has shown some early benefits in disease-free survival and has received approval for its use in adjuvant setting. In this article, we explore several reasons for this discrepancy in the results of CDK4/6 inhibitors in the adjuvant setting. We also question if we should already adopt adjuvant abemaciclib in our clinical practice given the uncertainty in data.

Keywords: Abemaciclib; Ki-67; Palbociclib; Ribociclib; disease-free survival; early stage breast cancer; overall survival

DOI: https://doi.org/10.3332/ecancer.2022.ed124

Anticancer Res. 2022 Oct;42(10): 4867-4878

Absolute Lymphocyte Count Is an Independent Prognostic Factor for ER-positive HER2-negative Advanced Breast Cancer Patients Treated With CDK4/6 Inhibitors.

Haruka Kanaoka, Masayuki Nagahashi, Yusa Atake, Akira Hattori, Ayako Bun, Reiko Fukui, Hiromi Ozawa, Yukie Fujimoto, Tomoko Higuchi, Keiko Natori, Michiko Imamura, Keiko Murase, Yuichi Takatsuka, Yasuo Miyoshi.

BACKGROUND/AIM: The aim of this study was to elucidate the clinical significance of peripheral blood biomarkers, including absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and C-reactive protein (CRP) in patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer treated with the CDK4/6 inhibitors, abemaciclib and palbociclib.
PATIENTS AND METHODS: A total of 83 patients treated with fulvestrant plus abemaciclib or palbociclib were included in this study. Progression-free survival (PFS) and overall survival (OS) were compared in relation to baseline levels of ALC, NLR, PLR and CRP.
RESULTS: The cut-off values of ALC, NLR, PLR, and CRP for PFS were determined from the receiver operating characteristic curve using the Youden index for area under the curve and set at 1,212/μl, 1.964, 170 and 0.220 mg/dl, respectively. In the abemaciclib-treated group, ALC-high patients showed significantly better PFS than ALC-low patients (p=0.0151) and multivariate analysis revealed that ALC was an independent prognostic factor for PFS (p=0.0085). In the palbociclib-treated group, there was no significant relationship between any peripheral blood biomarkers and PFS. In both treatment groups, ALC-high patients showed significantly better OS than ALC-low patients (p=0.0169 and 0.0290, respectively). Multivariate analysis revealed ALC was an independent prognostic factor for OS in both abemaciclib- and palbociclib-treated groups (p=0.0112 and 0.0202, respectively).
CONCLUSION: ALC is an independent prognostic factor for estrogen receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer patients treated with the CDK4/6 inhibitors abemaciclib and palbociclib.

Keywords: Advanced breast cancer; CDK4/6 inhibitor; absolute lymphocyte count; peripheral blood biomarker; prognostic factor

DOI: https://doi.org/10.21873/anticanres.15992

Breast. 2022 Sep 28. pii: S0960-9776(22)00160-6. [Epub ahead of print]66 77-84

Safety and efficacy of ribociclib plus letrozole in patients with HR+, HER2- advanced breast cancer: Results from the Spanish sub-population of the phase 3b CompLEEment-1 trial.

BACKGROUND: Breast cancer is the most common malignancy and the second leading cause of cancer-related mortality in Spanish women. Ribociclib in combination with endocrine therapy (ET) has shown superiority in prolonging survival in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) vs. ET alone.
METHODS: CompLEEment-1 is a single-arm, open-label phase 3b trial evaluating ribociclib plus letrozole in a broad population of patients with HR+, HER2- ABC. The primary endpoints were safety and tolerability. Here we report data for Spanish patients enrolled in CompLEEment-1.
RESULTS: A total of 526 patients were evaluated (median follow-up: 26.97 months). Baseline characteristics showed a diverse population with a median age of 54 years. At study entry, 56.5% of patients had visceral metastases and 8.7% had received prior chemotherapy for advanced disease. Rates of all-grade and Grade ≥3 adverse events (AEs) were 99.0% and 76.2%, respectively; 21.3% of patients experienced a serious AE, and 15.8% of AEs led to treatment discontinuation. AEs of special interest of neutropenia, increased alanine aminotransferase, increased aspartate aminotransferase and QTcF prolongation occurred in 77.8%, 14.8%, 11.4% and 4.0% of patients, respectively. Patients aged >70 years experienced increased rates of all-grade and Grade ≥3 neutropenia and anemia. Efficacy results were consistent with the global study.
CONCLUSIONS: Results from Spanish patients enrolled in CompLEEment-1 are consistent with global data showing efficacy and a manageable safety profile for ribociclib plus letrozole treatment in patients with HR+, HER2- ABC, including populations of interest (NCT02941926).
TRIAL REGISTRATION: ClinicalTrials.gov NCT02941926.

Keywords: Advanced breast cancer; CDK4/6 inhibitor; Postmenopausal; Premenopausal; Ribociclib

DOI: https://doi.org/10.1016/j.breast.2022.09.006

Anticancer Res. 2022 Oct;42(10): 4813-4824

Total Lesion Glycolysis Levels as Predictive Indicators in Patients With Metastatic and Recurrent Breast Cancer Undergoing Endocrine Therapy With or Without CDK4/6 Inhibitor.

Hiromi Ozawa, Tomoko Higuchi, Yukie Fujimoto, Ayako Bun, Reiko Fukui, Haruka Kanaoka, Masayuki Nagahashi, Kazuhiro Kitajima, Koichiro Yamakado, Yasuo Miyoshi.

BACKGROUND/AIM: Endocrine therapy (ET) with or without CDK4/6 inhibitors is the primary treatment choice for patients with estrogen receptor (ER)-positive and HER2-negative subtype of metastatic breast cancer (MBC). We examined the metabolic parameters identified using 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) in terms of sensitivity, since no predictive factors exist.
PATIENTS AND METHODS: We included 136 patients with MBC treated with ET alone (n=107) or combined with CDK4/6 inhibitor (n=29) and examined using FDG-PET before treatment began. The highest maximum value of the standard uptake value (SUVmax), whole-body metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated.
RESULTS: Progression-free survival (PFS) was significantly longer in patients with low levels of MTV, TLG, and SUVmax than those with higher levels (median PFS 49.5 vs. 20.7 months, p=0.001 for MTV, 49.5 vs. 20.7 months, p=0.0016 for TLG, 37.0 vs. 20.7 months, p=0.012 for SUVmax). Multivariable analysis revealed that TLG (hazard ratio=6.383, 95% confidence interval=1.167-34.913, p=0.033) was independently and significantly associated with PFS. The relationship between TLG levels and PFS was significant in patients treated with ET with (p=0.0054) and without (p=0.0188) CDK4/6 inhibitor.
CONCLUSION: TLG at baseline was a significant predictor for sensitivity to ET alone or combined with CDK4/6 inhibitor. These data may be useful to identify patients that would benefit from ET.

Keywords: 18F-fluorodeoxyglucose-positron emission tomography; Breast cancer; CDK4/6 inhibitor; endocrine therapy; predictive factor

DOI: https://doi.org/10.21873/anticanres.15986

Geburtshilfe Frauenheilkd. 2022 Oct;82(10): 1055-1067

Implementation of CDK4/6 Inhibitors and its Influence on the Treatment Landscape of Advanced Breast Cancer Patients - Data from the Real-World Registry PRAEGNANT.

Background Comprehensive data from prospective clinical trials have led to a high level of evidence establishing CDK4/6 inhibitors in combination with endocrine treatment (CDK4/6i + ET) as a standard for the treatment of HER2-negative, hormone receptor-positive (HER2- HR+) breast cancer patients in the first-line advanced therapy setting. Data on patient populations that have been treated in the real-world setting may provide an insight into changes of patient characteristics and prognosis over time. Methods The data were extracted from the prospective real-world registry PRAEGNANT (NCT02338167). Patients had to have HER2- HR+ advanced breast cancer in the first-line metastatic setting. The chosen therapies were described as well as progression-free survival (PFS) and overall survival (OS) in relation to the given therapies and time periods during which they were indicated. Results CDK4/6 inhibitors have been rapidly implemented since their introduction in November 2016. In recent years (2018 - 2022), about 70 - 80% of the patient population have been treated with CDK4/6 inhibitors, while endocrine monotherapy was given to about 10% and chemotherapy to about 15% of all patients. The prognosis was worst in patients treated with chemotherapy. Recently, mainly patients with a good prognosis are being treated with endocrine monotherapy, and patients who are treated with chemotherapy have an unfavorable prognosis. The PFS and OS of patients treated with CDK4/6i + ET have remained similar over time despite changes in patient characteristics. Conclusion A treatment with CDK4/6i + ET has rapidly become the therapy standard for patients in the first-line advanced breast cancer setting. After the implementation of CDK4/6i + ET, endocrine monotherapy is only given to patients with a very favorable prognosis, while chemotherapy is provided to patients with a rather unfavorable prognosis. These changes in patient characteristics did not seem to influence the prognosis of patients treated with CDK4/6i + ET.

Keywords: CDK4/6 inhibitor; advanced breast cancer; chemotherapy; endocrine treatment; real world data

DOI: https://doi.org/10.1055/a-1880-0087

Lancet Oncol. 2022 Sep 29. pii: S1470-2045(22)00555-1. [Epub ahead of print]

Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial.

PADA-1 investigators

BACKGROUND: In advanced oestrogen receptor-positive, HER2-negative breast cancer, acquired resistance to aromatase inhibitors frequently stems from ESR1-mutated subclones, which might be sensitive to fulvestrant. The PADA-1 trial aimed to show the efficacy of an early change in therapy on the basis of a rising ESR1 mutation in blood (bESR1mut), while assessing the global safety of combination fulvestrant and palbociclib.
METHODS: We did a randomised, open-label, phase 3 trial in 83 hospitals in France. Women aged at least 18 years with oestrogen receptor-positive, HER2-negative advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited and monitored for rising bESR1mut during first-line aromatase inhibitor (2·5 mg letrozole, 1 mg anastrozole, or 25 mg exemestane, orally once per day, taken continuously) and palbociclib (125 mg orally once per day on days 1-21 of a 28-day cycle) therapy. Patients with newly present or increased bESR1mut in circulating tumour DNA and no synchronous disease progression were randomly assigned (1:1) to continue with the same therapy or to switch to fulvestrant (500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1) and palbociclib (dosing unchanged). The randomisation sequence was generated within an interactive web response system using a minimisation method (with an 80% random factor); patients were stratified according to visceral involvement (present or absent) and the time from inclusion to bESR1mut detection (<12 months or ≥12 months). The co-primary endpoints were investigator-assessed progression-free survival from random assignment, analysed in the intention-to-treat population (ie, all randomly assigned patients), and grade 3 or worse haematological adverse events in all patients. The trial is registered with Clinicaltrials.gov (NCT03079011), and is now complete.
FINDINGS: From March 22, 2017, to Jan 31, 2019, 1017 patients were included, of whom 279 (27%) developed a rising bESR1mut and 172 (17%) were randomly assigned to treatment: 88 to switching to fulvestrant and palbociclib and 84 patients to continuing aromatase inhibitor and palbociclib. At database lock on July 31, 2021, randomly assigned patients had a median follow-up of 35·3 months (IQR 29·2-41·4) from inclusion and 26·0 months (13·8-34·3) from random assignment. Median progression-free survival from random assignment was 11·9 months (95% CI 9·1-13·6) in the fulvestrant and palbociclib group versus 5·7 months (3·9-7·5) in the aromatase inhibitor and palbociclib group (stratified HR 0·61, 0·43-0·86; p=0·0040). The most frequent grade 3 or worse haematological adverse events were neutropenia (715 [70·3%] of 1017 patients), lymphopenia (66 [6·5%]), and thrombocytopenia (20 [2·0%]). The most common grade 3 or worse adverse events in step 2 were neutropenia (35 [41·7%] of 84 patients in the aromatase inhibitor and palbociclib group vs 39 [44·3%] of 88 patients in the fulvestrant and palbociclib group) and lymphopenia (three [3·6%] vs four [4·5%]). 31 (3·1%) patients had grade 3 or worse serious adverse events related to treatment in the overall population. Three (1·7%) of 172 patients randomly assigned had one serious adverse event in step 2: one (1·2%) grade 4 neutropenia and one (1·2%) grade 3 fatigue among 84 patients in the aromatase inhibitor and palbociclib group, and one (1·1%) grade 4 neutropenia among 88 patients in the fulvestrant and palbociclib group. One death by pulmonary embolism in step 1 was declared as being treatment related.
INTERPRETATION: PADA-1 is the first prospective randomised trial showing that the early therapeutic targeting of bESR1mut results in significant clinical benefit. Additionally, the original design explored in PADA-1 might help with tackling acquired resistance with new drugs in future trials.
FUNDING: Pfizer.

DOI: https://doi.org/10.1016/S1470-2045(22)00555-1

Drugs. 2022 Oct 07.

Emerging Targeted Therapies for Early Breast Cancer.

Ilana Schlam, Paolo Tarantino, Stefania Morganti, Filipa Lynce, Dario Trapani, Erica L Mayer, Ana C Garrido-Castro, Ada Waks, Sara M Tolaney.

Breast cancer is the most common malignancy and the second leading cause of cancer-related mortality in the United States (US). Most patients are diagnosed with early-stage disease; however, there is still a need to prevent recurrences that often present as incurable metastatic disease. The treatment landscape of early-stage breast cancer is evolving rapidly. The immune checkpoint inhibitor pembrolizumab is approved in combination with neoadjuvant chemotherapy for the treatment of high-risk triple-negative breast cancer (TNBC). The cyclin-dependent kinase (CDK) 4 and 6 inhibitor abemaciclib is approved for adjuvant treatment of patients with high-risk hormone receptor (HR)-positive disease. While adjuvant olaparib has shown significant improvement in outcomes for patients with pathogenic/likely pathogenic BRCA1/2 mutations and high-risk human epidermal growth factor receptor 2 (HER2)-negative breast cancer, and is approved in this setting. For the HER2-positive subtype, the post-neoadjuvant therapy can be tailored based on the response to neoadjuvant chemotherapy and HER2-targeted agents. In this narrative review, we summarize the most recent approvals for early-stage breast cancer as well as frequently encountered clinical challenges utilizing these medications.

DOI: https://doi.org/10.1007/s40265-022-01781-5