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Purpose: To evaluate the efficacy and safety of the combination of olaparib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC) and germinal BRCA mutations (gBRCAm). Methods: OPHELIA (NCT03931551) was a single-arm, open-label, phase 2 clinical trial. Patients aged ≥18 years diagnosed with HER2-positive ABC with germinal deleterious mutations in BRCA1 or BRCA2 who had received at least one prior systemic regimen for advanced disease were enrolled. Patients received olaparib plus trastuzumab until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was investigator-assessed clinical benefit rate for at least 24 weeks as per RECIST v.1.1. Key secondary endpoints included overall response rate (ORR) and safety profile. Results: A total of 68 pre-treated HER2-positive ABC patients were screened. Due to slow accrual the trial was stopped after enrolling 5 patients instead of the planned sample size of 20. Four patients achieved clinical benefit (80.0 %, 95 % CI; 28.4–99.5, p

Background: The capsule formulation of CDK4/6 inhibitor palbociclib has reduced solubility at gastric pH > 4.5 and may have decreased activity when used with proton-pump inhibitors (PPI). Herein, we report the effect of PPI on palbociclib capsule activity and safety in the PARSIFAL study. Methods: First-line endocrine-sensitive, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) patients received palbociclib capsules plus fulvestrant or letrozole. The primary endpoint was progression-free survival (PFS). This post-hoc analysis compared PPI use. Patients were PPI-naïve (N-PPI) if not on PPI during the study, and either early (E-PPI) or long-term PPI (LT-PPI) if on PPI at study entry or for at least ≥⅔ of treatment, respectively. PPI groups were not mutually exclusive. Results: Among 486 patients, 66.9 % were N-PPI, 13.2 % E-PPI, 18.7 % LT-PPI, and 11.5 % of the PPI users were defined as neither. Median PFS (mPFS) was 29.6 months in the study population, 28.7 months in N-PPI, 23.0 months in E-PPI (Hazard Ratio [HR] 1.5; 95%Confidence Interval [CI] 1.1–2.2; p = 0.024), and 23.0 months in LT-PPI (HR 1.4; 95%CI 1.0–1.9; p = 0.035). By landmark analysis, PPI use was associated with poorer mPFS at 3 and 12 months. Grade ≥3 hematological adverse events occurred in 71.7 % of N-PPI, 57.8 % of E-PPI (p = 0.021), and 54.9 % of LT-PPI (p = 0.003). Dose reductions and dosing delays due to hematological toxicity occurred in 70.8 % of N-PPI, 56.3 % of E-PPI (p = 0.018), and 52.7 % of LT-PPI (p = 0.002). Conclusions: PPI use may reduce palbociclib capsule toxicity, dose modifications, and clinical activity in HR+/HER2- ABC.

Over the past few decades, first-line therapy for treating advanced and metastatic HR+/HER2-breast cancer has transformed due to the introduction of adjuvant endocrine therapy with cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i). However, there is an unmet need for novel classes of endocrine therapy with superior efficacy to improve treatment outcomes and overcome CDK4/6i resistance. New generation selective estrogen receptor degraders (SERDs), orally administered and with higher bioavailability, could potentially be the novel compounds to meet this emerging need. In this paper, we review accredited clinical studies on the combining effects of CDK4/6 inhibitors and oral SERDs, report efficacy of treatment data when available, and provide a framework for future research focusing on these promising agents.

The sustainability of healthcare systems is under pressure. Unlike care for many other chronic diseases, cancer care has yet to empower patients in effectively self-managing both the medical and emotional consequences of their condition, including adapting to changes in lifestyle and work, which is essential to achieve optimal health and recovery. Although proposed as a potential solution for sustainable healthcare and support for optimal health and recovery already decades ago, practical implementation of digital care lags behind.We believe electronic patient reported outcome measures (ePROMs) could play an important role in creating sustainable healthcare, both to guide complex treatment pathways and to empower survivors to self-manage consequences of diagnosis and treatment. That is, ePROMs can be used for screening and monitoring of symptoms, but also for treatment decision-making and to facilitate communication about quality of life. We therefore see opportunities for improvements in quality of care, quality of life, and survival of cancer patients, as well as research opportunities, as ePROMs collection can lead to better understanding of care needs. The ‘10 Actions for Change report’ of the Advanced Breast Cancer Global Alliance stresses a critical need for improvement of care for metastatic breast cancer (MBC) patients. We therefore in this paper focus on MBC care and research.

Purpose: This phase II study evaluated the impact of adding ribociclib to maintenance endocrine therapy (ET) treatment of physicians’ choice following the first palliative chemotherapy in pre- and post-menopausal women with hormone receptor positive (HR+)/human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (mBC). Patients and methods: The initial randomized study design was later amended into a single-arm study, and all subsequent patients received ribociclib and ET. The primary end point was locally assessed progression-free survival (PFS). Secondary end points included overall survival (OS), clinical benefit rate (CBR), safety, compliance, and quality of life (QoL). Results: A total of 43 patients received ribociclib + ET and 10 patients received ET only. Median PFS was 12.4 months [95% CI 8.7–24.4] for patients who received ribociclib + ET and 4.75 months [95% CI 1.0–10.3] for those who received ET only. Median OS was not reached for patients who received ribociclib + ET, and 28 (65.1%) patients experienced clinical benefit [95% CI 49.1–79.0]. For patients who received ribociclib + ET, grade 3–4 hematological adverse events (AEs) occurred in 25 (58.1%) patients, and grade 3–4 non-hematological AEs occurred in 17 (39.5%) patients. During the study, 15 patients died – 14 of whom due to tumor-related reasons, and one patient due to pneumonia, which was not treatment-related. Conclusion: The results of the AMICA study show a promising efficacy and safety of maintenance treatment with ribociclib added to ET after at least stable disease following the first metastatic chemotherapy in patients with HR+/HER2-mBC. Trial registration: Anti-hormonal Therapy With Ribociclib in HR-positive/HER2- Negative Metastatic Breast Cancer (AMICA), NCT03555877, https://clinicaltrials.gov/ct2/show/NCT03555877.

Background: Previous analyses from the PALOMA-2 and PALOMA-3 studies showed that palbociclib (PAL) plus endocrine therapy (ET) prolongs time to first subsequent chemotherapy (TTC) versus placebo (PBO) plus ET in the overall population of patients with hormone receptor‒positive/human epidermal growth factor receptor 2‒negative (HR+/HER2−) advanced breast cancer (ABC). Here, we evaluated TTC in relevant patient subgroups. Methods: These post hoc analyses evaluated TTC by subgroup using data from 2 randomized, phase 3 studies of women with HR+/HER2− ABC. In PALOMA-2, postmenopausal patients previously untreated for ABC were randomized 2:1 to receive PAL (125 mg/day, 3/1-week schedule) plus letrozole (LET; 2.5 mg/day; n = 444) or PBO plus LET (n = 222). In PALOMA-3, premenopausal or postmenopausal patients whose disease had progressed after prior ET were randomized 2:1 to receive PAL (125 mg/day, 3/1-week schedule) plus fulvestrant (FUL; 500 mg; n = 347) or PBO plus FUL (n = 174). Results: First subsequent chemotherapy was received by 35.5% and 56.2% in PALOMA-2 and PALOMA-3 after progression on palbociclib plus ET or placebo plus ET. Across all subgroups analyzed, the median progression-free survival (PFS) was longer in the PAL plus ET arm than the PBO plus ET arm. TTC was longer with PAL plus ET versus PBO plus ET across the same patient subgroups in both studies. Conclusions: Across all subgroups, PAL plus ET versus PBO plus ET had longer median PFS and resulted in prolonged TTC in both the PALOMA-2 and PALOMA-3 studies.Pfizer Inc (NCT01740427, NCT01942135).

Upon its establishment for the treatment of metastatic breast cancer (mBC), continuing trastuzumab beyond disease progression was an important paradigm shift that became the recommendation by major guidelines. However, data supporting continuation of human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab beyond the second-line setting are limited, resulting in a lack of approval of, or access to, this therapeutic strategy in many countries. This study aimed to provide additional data on the continued use of trastuzumab and trastuzumab-based therapies in combination with chemotherapy (CT) as third-line treatment for patients with mBC. This open-cohort, retrospective, observational study used deidentified patient-level data from an electronic health record–derived database that included patients with mBC who initiated third-line treatment with trastuzumab-based therapy combined with CT (Tras + CT; n = 288) or CT alone (CT; n = 49). Patients who received Tras + CT had a longer weighted median overall survival vs those who received CT only: 20.6 months (95% CI, 18.3–26.4 months) vs 10.1 months (95% CI, 7.8–12.3 months), respectively (hazard ratio [HR], 0.29; 95% CI, 0.16–0.53). This study provides additional support for maintaining trastuzumab-based therapies for patients with HER2+ mBC beyond second-line treatment. This treatment option should be available for all patients with mBC worldwide.

Human epidermal growth factor receptor 2 oncogene (HER2-positive) overexpression/amplification occurs in less than 20% of breast cancers and has traditionally been associated with poor prognosis. Development of therapies that target HER2 has significantly improved outcomes for patients with HER2-positive advanced breast cancer (ABC). Currently available HER2-targeted agents include the monoclonal antibodies trastuzumab, pertuzumab, and margetuximab, the small-molecule inhibitors lapatinib, tucatinib, neratinib, and pyrotinib, as well as the antibody-drug conjugates trastuzumab emtansine and trastuzumab deruxtecan. Optimal sequencing of these agents in the continuum of the disease is critical to maximize treatment outcomes. The large body of clinical evidence generated over the past 2 decades aids clinicians in treatment decision-making. However, patients with HER2-positive ABC and specific disease characteristics and/or comorbidities, such as leptomeningeal disease, brain metastases, or cardiac dysfunction, are generally excluded from large randomized clinical trials, and elderly or frail patients are often underrepresented. In addition, there is great inequality in the accessibility of approved drugs across countries. This article addresses various challenging clinical situations when treating patients with HER2-positive ABC. The objective is to provide guidance to clinicians on how and when HER2-targeted therapies and additional treatments can be best implemented in routine clinical practice, on the basis of existing clinical evidence and expert opinion where needed.

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

Background: People with advanced breast cancer (ABC) in New Zealand (NZ) have a poorer five-year survival than their peers in other developed countries. Comparisons of ABC care in NZ with other countries suggest that NZ is sometimes out of line with international standards and that inequities exist within the NZ healthcare system. Our aim was to develop nationwide consensus guidelines for diagnosis and treatment of ABC that are uniquely suited for the NZ context and can be applied across the nation. We describe the process of creating, voting on, and disseminating the guidelines, and provide insight into how we can better optimize these processes for the NZ context in the future. Methods: The ABC5 ESO-ESMO consensus guidelines were used and adapted to the NZ clinical context. A panel of breast cancer clinicians voted on these guidelines using the same model of membership representation as ABC5. Outcome: Overall consensus was equally high between ABC5 and ABC-NZ. Four NZ specific guidelines were introduced. The European-style panel discussion needs some adaptations for the NZ situation and a wider and more thorough consultation process, before voting begins, is preferred. The NZ Breast Special Interest Group has endorsed and agreed to take ownership of these and future guidelines and to facilitate the next iteration of the ABC-NZ guidelines meeting. Conclusions: The process was successful in creating the guidelines but can be improved in future meetings to streamline the process of creating and updating guidelines in the manner most suited to the NZ context and audience.

Previous analyses from the PALOMA-2 and PALOMA-3 studies showed that palbociclib (PAL) plus endocrine therapy (ET) prolongs time to first subsequent chemotherapy (TTC) versus placebo (PBO) plus ET in the overall population of patients with hormone receptor‒positive/human epidermal growth factor receptor 2‒negative (HR+/HER2−) advanced breast cancer (ABC). Here, we evaluated TTC in relevant patient subgroups. These post hoc analyses evaluated TTC by subgroup using data from 2 randomized, phase 3 studies of women with HR+/HER2− ABC. In PALOMA-2, postmenopausal patients previously untreated for ABC were randomized 2:1 to receive PAL (125 mg/day, 3/1-week schedule) plus letrozole (LET; 2.5 mg/day; n = 444) or PBO plus LET (n = 222). In PALOMA-3, premenopausal or postmenopausal patients whose disease had progressed after prior ET were randomized 2:1 to receive PAL (125 mg/day, 3/1-week schedule) plus fulvestrant (FUL; 500 mg; n = 347) or PBO plus FUL (n = 174). First subsequent chemotherapy was received by 35.5% and 56.2% in PALOMA-2 and PALOMA-3 after progression on palbociclib plus ET or placebo plus ET. Across all subgroups analyzed, the median progression-free survival (PFS) was longer in the PAL plus ET arm than the PBO plus ET arm. TTC was longer with PAL plus ET versus PBO plus ET across the same patient subgroups in both studies. Across all subgroups, PAL plus ET versus PBO plus ET had longer median PFS and resulted in prolonged TTC in both the PALOMA-2 and PALOMA-3 studies. Pfizer Inc (NCT01740427, NCT01942135). • Palbociclib + endocrine therapy prolongs time to chemotherapy in HR+/HER2– cancer. • We analyzed palbociclib efficacy data from 2 clinical trials across subgroups. • Patient subgroups were based on demographics and baseline disease characteristics. • Palbociclib increased progression-free survival versus placebo across all subgroups. • Palbociclib increased time to chemotherapy versus placebo across all subgroups. [ABSTRACT FROM AUTHOR]

Upon its establishment for the treatment of metastatic breast cancer (mBC), continuing trastuzumab beyond disease progression was an important paradigm shift that became the recommendation by major guidelines. However, data supporting continuation of human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab beyond the second-line setting are limited, resulting in a lack of approval of, or access to, this therapeutic strategy in many countries. This study aimed to provide additional data on the continued use of trastuzumab and trastuzumab-based therapies in combination with chemotherapy (CT) as third-line treatment for patients with mBC. This open-cohort, retrospective, observational study used deidentified patient-level data from an electronic health record–derived database that included patients with mBC who initiated third-line treatment with trastuzumab-based therapy combined with CT (Tras + CT; n = 288) or CT alone (CT; n = 49). Patients who received Tras + CT had a longer weighted median overall survival vs those who received CT only: 20.6 months (95% CI, 18.3–26.4 months) vs 10.1 months (95% CI, 7.8–12.3 months), respectively (hazard ratio [HR], 0.29; 95% CI, 0.16–0.53). This study provides additional support for maintaining trastuzumab-based therapies for patients with HER2+ mBC beyond second-line treatment. This treatment option should be available for all patients with mBC worldwide. • Tras-based regimens post progression are not universally approved or reimbursed. • Tras + CT doubled OS as third-line therapy for HER2+ mBC compared with CT alone. • Real-world data support continuing HER2 blockade beyond second line for HER2+ mBC. • Tras-based therapies must be available to all HER2+ mBC patients beyond progression. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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). ClinicalTrials.gov NCT02941926 • Results from the CompLEEment-1 Spanish population are comparable to the global results. • Manageable safety was shown in elderly patients and those with visceral disease. • Efficacy data were comparable to those of the global study in a younger population. • Efficacy and safety of ribociclib are confirmed in a broader patient population. • Results confirm a robust response to treatment in a local setting. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 oncogene (HER2-positive) overexpression/amplification occurs in less than 20% of breast cancers and has traditionally been associated with poor prognosis. Development of therapies that target HER2 has significantly improved outcomes for patients with HER2-positive advanced breast cancer (ABC). Currently available HER2-targeted agents include the monoclonal antibodies trastuzumab, pertuzumab, and margetuximab, the small-molecule inhibitors lapatinib, tucatinib, neratinib, and pyrotinib, as well as the antibody-drug conjugates trastuzumab emtansine and trastuzumab deruxtecan. Optimal sequencing of these agents in the continuum of the disease is critical to maximize treatment outcomes. The large body of clinical evidence generated over the past 2 decades aids clinicians in treatment decision-making. However, patients with HER2-positive ABC and specific disease characteristics and/or comorbidities, such as leptomeningeal disease, brain metastases, or cardiac dysfunction, are generally excluded from large randomized clinical trials, and elderly or frail patients are often underrepresented. In addition, there is great inequality in the accessibility of approved drugs across countries. This article addresses various challenging clinical situations when treating patients with HER2-positive ABC. The objective is to provide guidance to clinicians on how and when HER2-targeted therapies and additional treatments can be best implemented in routine clinical practice, on the basis of existing clinical evidence and expert opinion where needed. HER2-targeted therapies have significantly improved outcomes for patients with ABC Ideal sequencing of regimens is key to maximize treatment benefits New HER2-targeted agents are used at earlier stages in BC treatment Clinical evidence for treatment of special populations with ABC is lacking Approved drugs are not accessible in all countries [ABSTRACT FROM AUTHOR]

Background: The phase IIIb CompLEEment-1 study evaluated ribociclib plus letrozole in patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC). Outcomes were investigated in the following subgroups: central nervous system (CNS) metastases, prior chemotherapy for advanced disease, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, and visceral metastases plus prior chemotherapy for advanced disease or ECOG PS 2. Patients and methods: Patients with HR+, HER2– ABC without prior hormonal treatment for advanced disease received oral ribociclib (600 mg once daily, 3 weeks on/1 week off) plus letrozole (2.5 mg once daily, continuous). Primary endpoint was safety/tolerability, assessed via occurrence of adverse events (AEs); key secondary endpoints included time to progression (TTP), overall response rate, and clinical benefit rate. Results: 51 patients had CNS metastases, 194 received prior chemotherapy for advanced disease, 112 had ECOG PS 2, 146 had visceral metastases plus prior chemotherapy, and 77 had visceral metastases plus ECOG PS 2. Safety results were consistent with those in the overall CompLEEment-1 population; no new safety concerns were identified. The AE profile was manageable with low rates of discontinuations due to AEs. TTP in patients with CNS metastases was consistent with the overall study population and shorter for other patient subgroups. Each patient subgroup achieved meaningful clinical benefit from treatment, consistent with the overall population. Conclusion: These findings confirm the clinical benefit of ribociclib plus endocrine therapy in high-risk patient subgroups of clinical interest commonly underrepresented in clinical trials.

Background: Real-world (RW) data may provide valuable information on the effectiveness and safety of medicines, which is particularly relevant for clinicians, patients and third-party payers. Evidence on the effectiveness of palbociclib plus fulvestrant is scarce, which highlights the need of additional studies. The aim of this study was to evaluate the effectiveness of palbociclib plus fulvestrant in advanced breast cancer (ABC). Materials and methods: We conducted a population-based retrospective cohort study and cases of interest were identified through the Portuguese National Cancer Registry database and additional data sources. Patients aged≥18 years, diagnosed with ABC and exposed to palbociclib plus fulvestrant between May 31, 2017 and March 31, 2019 were included. Patients were followed-up until death or cut-off date (February 28, 2021). Primary outcome was rw-progression-free survival (rwPFS). Secondary outcomes were rw-overall survival (rwOS), rw-time to palbociclib failure (rwTPF) and rw-time to next treatment (rwTTNT). Results: A total of 210 patients were included. Median age was 58 years (range 29–83) and 99.05% were female. Median follow-up time was 23.22 months and, at cut-off date, treatment had been discontinued in 189 patients, mainly due to disease progression (n = 152). Median rwPFS was 7.43 months (95% confidence interval [CI] 6.28–9.05) and 2-year rwPFS was 16.65% (95%CI 11.97–22.00). Median rwOS was 24.70 months (95%CI 21.58–29.27), median rwTPF was 7.5 months (95%CI 6.51–9.08) and median rwTTNT was 11.74 months (95%CI 10.33–14.08). Conclusion: Palbociclib plus fulvestrant seems an effective treatment for ABC in real-world context. Compared to registrations studies, rwPFS and rwOS were shorter in real-life setting.

To evaluate the efficacy and safety of the combination of olaparib plus trastuzumab in patients with HER2-positive advanced breast cancer (ABC) and germinal BRCA mutations (gBRCAm). OPHELIA (NCT03931551) was a single-arm, open-label, phase 2 clinical trial. Patients aged ≥18 years diagnosed with HER2-positive ABC with germinal deleterious mutations in BRCA1 or BRCA2 who had received at least one prior systemic regimen for advanced disease were enrolled. Patients received olaparib plus trastuzumab until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was investigator-assessed clinical benefit rate for at least 24 weeks as per RECIST v.1.1. Key secondary endpoints included overall response rate (ORR) and safety profile. A total of 68 pre-treated HER2-positive ABC patients were screened. Due to slow accrual the trial was stopped after enrolling 5 patients instead of the planned sample size of 20. Four patients achieved clinical benefit (80.0 %, 95 % CI; 28.4–99.5, p < 0.001) and the primary endpoint was met. The ORR was 60.0 % (95 % CI; 14.7–94.7), including one complete response. Four (80.0 %) patients experienced at least one treatment-related treatment-emergent adverse event (TEAE). Most TEAEs were grade 1 or 2. There were no treatment-related deaths and no new safety signals were identified. This study suggests that the combination of olaparib plus trastuzumab may be effective and safe in pre-treated patients with HER2-positive g BRCA m ABC. This ABC patient population should be further studied and not be pre-emptively excluded from clinical trials of targeted therapy for BRCA1/2 -driven cancers. • HER2 overexpression in g BRCA m is infrequent. • Olaparib plus trastuzumab showed promising efficacy in patients with HER2-positive ABC and g BRCA m. • This patient population should not be excluded from clinical trials of targeted therapy for BRCA1/2 -driven cancers. [ABSTRACT FROM AUTHOR]

Objective: In the PALOMA-2 trial, palbociclib in combination with letrozole prolonged progression-free survival (PFS) and exhibited an acceptable safety profile in patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ABC). This post hoc analysis of PALOMA-2 evaluated the efficacy and safety of palbociclib plus letrozole in patients with preexisting conditions grouped by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC). Methods: Postmenopausal patients without prior treatment for ABC were randomized 2:1 to receive palbociclib (125 mg/d on a 3 weeks on/1 week off schedule) plus letrozole (2.5 mg/d, continuous) or placebo plus letrozole. Patients were grouped by the following MedDRA SOC preexisting conditions: gastrointestinal, musculoskeletal, metabolic, and vascular/cardiac. Median PFS was estimated by the Kaplan-Meier method, and treatment emergent adverse events (AEs) were compared between treatment arms within each preexisting condition subgroup. Results: At baseline, 276 (41.4 %) patients had preexisting gastrointestinal disorders, 390 (58.6 %) had musculoskeletal disorders, 259 (38.9 %) had metabolic disorders, and 382 (57.4 %) had vascular/cardiac disorders. Baseline characteristics were similar between subgroups and between each arm within subgroups. Regardless of baseline preexisting condition, palbociclib plus letrozole prolonged PFS compared with placebo plus letrozole. Treatment-emergent AEs associated with palbociclib plus letrozole and dose modifications due to AEs were similar across preexisting condition subgroups. Conclusion: This post hoc analysis of PALOMA-2 demonstrated a favorable effect of palbociclib on PFS and a safety profile consistent with previous observations, regardless of underlying preexisting condition. Pfizer Inc (NCT01740427).

People with advanced breast cancer (ABC) in New Zealand (NZ) have a poorer five-year survival than their peers in other developed countries. Comparisons of ABC care in NZ with other countries suggest that NZ is sometimes out of line with international standards and that inequities exist within the NZ healthcare system. Our aim was to develop nationwide consensus guidelines for diagnosis and treatment of ABC that are uniquely suited for the NZ context and can be applied across the nation. We describe the process of creating, voting on, and disseminating the guidelines, and provide insight into how we can better optimize these processes for the NZ context in the future. The ABC5 ESO-ESMO consensus guidelines were used and adapted to the NZ clinical context. A panel of breast cancer clinicians voted on these guidelines using the same model of membership representation as ABC5. Overall consensus was equally high between ABC5 and ABC-NZ. Four NZ specific guidelines were introduced. The European-style panel discussion needs some adaptations for the NZ situation and a wider and more thorough consultation process, before voting begins, is preferred. The NZ Breast Special Interest Group has endorsed and agreed to take ownership of these and future guidelines and to facilitate the next iteration of the ABC-NZ guidelines meeting. The process was successful in creating the guidelines but can be improved in future meetings to streamline the process of creating and updating guidelines in the manner most suited to the NZ context and audience. • Advanced breast cancer (ABC) care in New Zealand is applied inconsistently across patients. It often fails to meet international standards. • ABC care could benefit from creation and implementation of NZ-specific guidelines. • ABC5 guidelines were adapted to fit NZ context and some new NZ-specific guidelines were created. These were voted on by a multidisciplinary panel, leading to 115 guidelines for ABC care in New Zealand. • We report our experience with the process and plans to implement the guidelines and assess their uptake and efficacy. [ABSTRACT FROM AUTHOR]

Introduction: Neutropenia and diarrhoea are common and potentially serious adverse events associated with abemaciclib in advanced breast cancer (ABC), and the risk factors have been minimally explored. The study aimed to develop clinical prediction tools that allow personalized predictions of neutropenia and diarrhoea following abemaciclib initiation. Materials and methods: Data was pooled from MONARCH 1, 2 and 3 trials investigating abemaciclib. Cox proportional hazard analysis was used to assess the association between pre-treatment clinicopathological data and grade ≥3 diarrhoea and neutropenia occurring within the first 365 days of abemaciclib use. Results: Older age was associated with increased risk of grade ≥3 diarrhoea [HR [95%CI] for age > 70: 1.72 [1.14–2.58]; P = 0.009]. A clinical prediction tool for abemaciclib induced grade ≥3 neutropenia was optimally defined by race, ECOGPS and white blood cell count. Large discrimination between subgroups was observed; the highest risk subgroup had a 64% probability of grade ≥3 neutropenia within the first 365 days of abemaciclib (150 mg twice daily) + fulvestrant/NSAI, compared to 5% for the lowest risk subgroup. Conclusion: The study identified advanced age as significantly associated with an increased risk of abemaciclib induced grade ≥ 3 diarrhoea. A clinical prediction tool, defined by race, ECOGPS and pre-treatment white blood cell count, was able to discriminate subgroups with significantly different risks of grade ≥3 neutropenia following abemaciclib initiation. The tool may enable improved interpretation of personalized risks and the risk-benefit ratio of abemaciclib.

The capsule formulation of CDK4/6 inhibitor palbociclib has reduced solubility at gastric pH > 4.5 and may have decreased activity when used with proton-pump inhibitors (PPI). Herein, we report the effect of PPI on palbociclib capsule activity and safety in the PARSIFAL study. First-line endocrine-sensitive, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) patients received palbociclib capsules plus fulvestrant or letrozole. The primary endpoint was progression-free survival (PFS). This post-hoc analysis compared PPI use. Patients were PPI-naïve (N-PPI) if not on PPI during the study, and either early (E-PPI) or long-term PPI (LT-PPI) if on PPI at study entry or for at least ≥⅔ of treatment, respectively. PPI groups were not mutually exclusive. Among 486 patients, 66.9 % were N-PPI, 13.2 % E-PPI, 18.7 % LT-PPI, and 11.5 % of the PPI users were defined as neither. Median PFS (mPFS) was 29.6 months in the study population, 28.7 months in N-PPI, 23.0 months in E-PPI (Hazard Ratio [HR] 1.5; 95%Confidence Interval [CI] 1.1–2.2; p = 0.024), and 23.0 months in LT-PPI (HR 1.4; 95%CI 1.0–1.9; p = 0.035). By landmark analysis, PPI use was associated with poorer mPFS at 3 and 12 months. Grade ≥3 hematological adverse events occurred in 71.7 % of N-PPI, 57.8 % of E-PPI (p = 0.021), and 54.9 % of LT-PPI (p = 0.003). Dose reductions and dosing delays due to hematological toxicity occurred in 70.8 % of N-PPI, 56.3 % of E-PPI (p = 0.018), and 52.7 % of LT-PPI (p = 0.002). PPI use may reduce palbociclib capsule toxicity, dose modifications, and clinical activity in HR+/HER2- ABC. • Concomitant proton pump inhibitor and palbociclib was retrospectively analyzed. • Median progression-free survival was shorter with proton pump inhibitor use. • Adverse events and dose reductions were lower with proton pump inhibitors. • These results reveal proton pump inhibitors may interact with palbociclib capsules. [ABSTRACT FROM AUTHOR]

Over the past few decades, first-line therapy for treating advanced and metastatic HR+/HER2-breast cancer has transformed due to the introduction of adjuvant endocrine therapy with cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i). However, there is an unmet need for novel classes of endocrine therapy with superior efficacy to improve treatment outcomes and overcome CDK4/6i resistance. New generation selective estrogen receptor degraders (SERDs), orally administered and with higher bioavailability, could potentially be the novel compounds to meet this emerging need. In this paper, we review accredited clinical studies on the combining effects of CDK4/6 inhibitors and oral SERDs, report efficacy of treatment data when available, and provide a framework for future research focusing on these promising agents. • Oral SERDs have come forward as a promising alternative to fulvestrant. • Elacestrant and camizestrant improved PFS in ER+/HER2-advanced or metastatic breast cancer, especially with ESR1 mutations. • Elacestrant is the first approved oral SERD, after showing efficacy and good tolerability especially in ESR1 mutated tumors. • Oral SERDs exhibit potential to be established as new combination agents along with CDK4/6 inhibitors. [ABSTRACT FROM AUTHOR]

Purpose: Treatment with CDK4/6 inhibitors and endocrine therapy (CDK4/6i + ET) is a standard for patients with advanced hormone receptor–positive, HER2-negative (HR + HER2–) breast cancer (BC). However, real-world data on the implementation of therapy usage, efficacy, and toxicity have not yet been reported. Methods: The PRAEGNANT registry was used to identify advanced HR + HER2– BC patients (n = 1136). The use of chemotherapy, ET, everolimus + ET, and CDK4/6i + ET was analyzed for first-line, second-line, and third-line therapy. Progression-free survival (PFS) and overall survival (OS) were also compared between patients treated with CDK4/6i + ET and ET monotherapy. Also toxicity was assessed. Results: CDK4/6i + ET use increased from 38.5% to 62.7% in the first 2 years after CDK4/6i treatment became available (November 2016). Chemotherapy and ET monotherapy use decreased from 2015 to 2018 from 42.2% to 27.2% and from 53% to 9.5%, respectively. In this early analysis no statistically significant differences were found comparing CDK4/6i + ET and ET monotherapy patients with regard to PFS and OS. Leukopenia was was seen in 11.3% of patients under CDK4/6i + ET and 0.5% under ET monotherapy. Conclusions: In clinical practice, CDK4/6i + ET has been rapidly implemented. A group of patients with a more unfavorable prognosis was possibly treated in the real-world setting than in the reported randomized clinical trials. The available data suggest that longer follow-up times and a larger sample size are required in order to identify differences in survival outcomes. Studies should be supported that investigate whether chemotherapy can be avoided or delayed in this patient population by using CDK4/6i + ET.

Background: This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavily-pretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017. Patients and methods: Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR+/HER2- mBC who had progressed on ≥4 treatments for advanced disease were eligible. Results: A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7–7.0) and the median overall survival was 19.0 months (95% CI 16.4–21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus ≤6 months; HR 1.93, 95% CI 1.37–2.73, p

Background: Palbociclib is indicated for the treatment of hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC), in combination with endocrine therapy. Emerging real-life data suggest that the efficacy of a palbociclib-based therapy is highly conserved. We report the Institut Curie hospital experience. Patients and methods: We retrospectively reviewed all patients with HR + HER2- ABC treated with a palbociclib-based therapy as first or second line for ABC, with an initial prescription from November 2016 to December 2018. Clinical, laboratory and imaging data were retrieved from electronic records. Data lock was December 31st, 2019. Descriptive analyses, univariate and multivariate Cox regression analyses were performed. Results: We included 310 consecutive patients. Median age was 61.8 years old. Palbociclib was prescribed in first line in 225 patients (72.6%). Before palbociclib-based therapy initiation, 122 patients (39.3%) were endocrine naive, 96 (31.0%) endocrine sensitive and 92 (29.7%) endocrine resistant. Median follow-up was 20.7 months. Median progression free survival (PFS) was 23.4 months (95%CI: 21.6-NR) in endocrine naive patients, 22.7 months (95%CI: 14.7-NR) in endocrine sensitive, and 13.4 months (95%CI: 10.7–20.8) in endocrine resistant. At 12 months from the initiation of palbociclib, 94.5% of patients were alive. By multivariate analysis, poor prognosis factors for PFS were identified in the endocrine naive/sensitive population: initial ECOG status 2, previous endocrine therapy for ABC, 3 metastatic sites or more. Toxicity profile was similar to previously published data. Conclusion: In a non-selected population of patients with HR + HER2- ABC, the efficacy and safety data are strikingly similar to those previously reported.

Background: There is a lack of prognostic models predicting the overall survival (OS) of advanced breast cancer (ABC) patients in China. Methods: Data from the China National Cancer Center database that recorded 4039 patients diagnosed with breast cancer between 1987 and 2019 were extracted and a total of 2263 ABC participants were enrolled in this study, which were further randomized 3:1 and divided into training (n = 1706) and validation (n = 557) groups. The nomogram was built based on independent predictors identified by univariate and multivariate cox regression analyses. The discriminatory and predictive capacities of the nomogram were assessed by Harrell’s concordance index (C-index) and calibration plots. Results: Univariate and multivariate analyses found that age, Eastern Cooperative Oncology Group (ECOG) score, T-stage, N-stage, tumor subtype, the presence of distant lymph node (DLN)/liver/brain metastasis, local therapy, efficacy of first-line therapy and metastatic-free interval (MFI) were significantly related to OS (all P

Background. The combination of chemotherapy plus anti HER-2 agents is the mainstay of HER-2 positive advanced breast cancer (ABC) therapy. We conducted a phase II trial testing activity and safety of trastuzumab and metronomic capecitabine/cyclophosphamide (HEX) as first-line therapy in HER-2 positive ABC. Methods. Patients at first relapse or with synchronous metastasis were treated with trastuzumab (4 mg/kg, biweekly) plus oral capecitabine (1500 mg/daily) and cyclophosphamide (50 mg/daily). Primary endpoint was objective response rate (ORR), secondary endpoints progression-free survival (PFS), clinical benefit rate (CBR; PR + CR + SD for ≥ 24 weeks) and tolerability. Optimal two-stage design was applied. Results. Sixty patients with measurable ABC, tumors scored as +3 for HER-2 or FISH +, untreated for advanced disease were enrolled. Median age was 62.5 years, visceral metastases were present in most patients (57.9%). Median number of cycles was 16 (range 1–98). ORR was 56.7% (95% CI, 44.1–68.4%), with 5 CR (8.3%) and 29 PR (48.3%). Fifteen patients had SD (25%). The CBR was 78.2%. Nine progressions were observed (15%). Median PFS was 11 months. One year PFS was 47.7%. Median OS was 45.9 months. Worst toxicities were grade 3 hand-foot syndrome in 2 pts (3.3%), grade 3 anaemia in 2 pts (3.3%), grade 2 nausea in 2 pts (3.3%) and grade 3–4 diarrhea in 2 pts (3.3%). Cardiac toxicity grade 1 was reported in 1 pt. Conclusions. Combination of trastuzumab and metronomic oral chemotherapy has clinical activity. The tolerability was excellent and allowed the prolonged delivery of treatment.

In the PALOMA-2 trial, palbociclib in combination with letrozole prolonged progression-free survival (PFS) and exhibited an acceptable safety profile in patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer (ABC). This post hoc analysis of PALOMA-2 evaluated the efficacy and safety of palbociclib plus letrozole in patients with preexisting conditions grouped by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC). Postmenopausal patients without prior treatment for ABC were randomized 2:1 to receive palbociclib (125 mg/d on a 3 weeks on/1 week off schedule) plus letrozole (2.5 mg/d, continuous) or placebo plus letrozole. Patients were grouped by the following MedDRA SOC preexisting conditions: gastrointestinal, musculoskeletal, metabolic, and vascular/cardiac. Median PFS was estimated by the Kaplan-Meier method, and treatment emergent adverse events (AEs) were compared between treatment arms within each preexisting condition subgroup. At baseline, 276 (41.4 %) patients had preexisting gastrointestinal disorders, 390 (58.6 %) had musculoskeletal disorders, 259 (38.9 %) had metabolic disorders, and 382 (57.4 %) had vascular/cardiac disorders. Baseline characteristics were similar between subgroups and between each arm within subgroups. Regardless of baseline preexisting condition, palbociclib plus letrozole prolonged PFS compared with placebo plus letrozole. Treatment-emergent AEs associated with palbociclib plus letrozole and dose modifications due to AEs were similar across preexisting condition subgroups. This post hoc analysis of PALOMA-2 demonstrated a favorable effect of palbociclib on PFS and a safety profile consistent with previous observations, regardless of underlying preexisting condition. Pfizer Inc (NCT01740427). • Preexisting conditions can affect the safety and efficacy of breast cancer therapies. • This is a post hoc analysis of patients with preexisting conditions from PALOMA-2. • Palbociclib prolonged median PFS, regardless of preexisting condition. • Within each treatment arm, AEs were similar regardless of preexisting condition. [ABSTRACT FROM AUTHOR]

Neutropenia and diarrhoea are common and potentially serious adverse events associated with abemaciclib in advanced breast cancer (ABC), and the risk factors have been minimally explored. The study aimed to develop clinical prediction tools that allow personalized predictions of neutropenia and diarrhoea following abemaciclib initiation. Data was pooled from MONARCH 1, 2 and 3 trials investigating abemaciclib. Cox proportional hazard analysis was used to assess the association between pre-treatment clinicopathological data and grade ≥3 diarrhoea and neutropenia occurring within the first 365 days of abemaciclib use. Older age was associated with increased risk of grade ≥3 diarrhoea [HR [95%CI] for age > 70: 1.72 [1.14–2.58]; P = 0.009]. A clinical prediction tool for abemaciclib induced grade ≥3 neutropenia was optimally defined by race, ECOGPS and white blood cell count. Large discrimination between subgroups was observed; the highest risk subgroup had a 64% probability of grade ≥3 neutropenia within the first 365 days of abemaciclib (150 mg twice daily) + fulvestrant/NSAI, compared to 5% for the lowest risk subgroup. The study identified advanced age as significantly associated with an increased risk of abemaciclib induced grade ≥ 3 diarrhoea. A clinical prediction tool, defined by race, ECOGPS and pre-treatment white blood cell count, was able to discriminate subgroups with significantly different risks of grade ≥3 neutropenia following abemaciclib initiation. The tool may enable improved interpretation of personalized risks and the risk-benefit ratio of abemaciclib. • Neutropenia and diarrhoea are common adverse effects of abemaciclib. • Higher age was associated with abemaciclib induced diarrhoea. • White blood cell count, Race, and performance status were linked with neutropenia. • A prediction tool was developed to provide personalized risks of neutropenia. [ABSTRACT FROM AUTHOR]

• This article reviews some of the most clinically relevant data related to metastatic breast cancer presented during 2023. • Elacestrant (oral SERD) was approved in 2023 for the treatment of patients with pretreated ESR1 mutant HR-positive mBC. • Capivasertib (AKT inhibitor) was approved in 2023 for patients with pretreated mBC with PIK3CA , PTEN , or AKT1 alterations. • Sacituzumab govitecan was approved in 2023 for patients with HR-positive tumors previously tereated with chemotherapy. [ABSTRACT FROM AUTHOR]

The sustainability of healthcare systems is under pressure. Unlike care for many other chronic diseases, cancer care has yet to empower patients in effectively self-managing both the medical and emotional consequences of their condition, including adapting to changes in lifestyle and work, which is essential to achieve optimal health and recovery. Although proposed as a potential solution for sustainable healthcare and support for optimal health and recovery already decades ago, practical implementation of digital care lags behind. We believe electronic patient reported outcome measures (ePROMs) could play an important role in creating sustainable healthcare, both to guide complex treatment pathways and to empower survivors to self-manage consequences of diagnosis and treatment. That is, ePROMs can be used for screening and monitoring of symptoms, but also for treatment decision-making and to facilitate communication about quality of life. We therefore see opportunities for improvements in quality of care, quality of life, and survival of cancer patients, as well as research opportunities, as ePROMs collection can lead to better understanding of care needs. The '10 Actions for Change report' of the Advanced Breast Cancer Global Alliance stresses a critical need for improvement of care for metastatic breast cancer (MBC) patients. We therefore in this paper focus on MBC care and research. • Electronic patient-reported outcome measures (PROMs) in clinical practice can be promising for sustainable healthcare. • Implementation of PROMs could address urgently needed improvements for metastatic breast cancer care. • This includes improvements in quality of care, quality of life, survival of cancer patients, and research opportunities. [ABSTRACT FROM AUTHOR]

This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavily-pretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017. Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR+/HER2- mBC who had progressed on ≥4 treatments for advanced disease were eligible. A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7–7.0) and the median overall survival was 19.0 months (95% CI 16.4–21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus ≤6 months; HR 1.93, 95% CI 1.37–2.73, p < 0.001). The most frequently reported toxicities were neutropenia, asthenia, thrombopenia and anemia. Palbociclib can be an effective and safe treatment option in patients with heavily pretreated endocrine-sensitive mBC, especially in those with longer PFS to previous ET. • CDK4/6 inhibitors combined with endocrine therapy have been widely accepted as a new standard therapy for hormone receptor-positive metastatic breast cancer patients in first or second line. • Palbociclib alone or in combination with aromatase inhibitors, fulvestrant, or tamoxifen was effective and safe in heavily pretreated HR+/HER2- metastatic breast cancer patients. • Palbociclib could be of higher benefit to patients with endocrine-sensitive disease that had a long duration of response to previous endocrine therapy. • Real-world evidence of effectiveness and safety of use of palbociclib in heavily pretreated advanced breast cancer patients complements data from randomized clinical trials. [ABSTRACT FROM AUTHOR]

Palbociclib is indicated for the treatment of hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC), in combination with endocrine therapy. Emerging real-life data suggest that the efficacy of a palbociclib-based therapy is highly conserved. We report the Institut Curie hospital experience. We retrospectively reviewed all patients with HR + HER2- ABC treated with a palbociclib-based therapy as first or second line for ABC, with an initial prescription from November 2016 to December 2018. Clinical, laboratory and imaging data were retrieved from electronic records. Data lock was December 31st, 2019. Descriptive analyses, univariate and multivariate Cox regression analyses were performed. We included 310 consecutive patients. Median age was 61.8 years old. Palbociclib was prescribed in first line in 225 patients (72.6%). Before palbociclib-based therapy initiation, 122 patients (39.3%) were endocrine naive, 96 (31.0%) endocrine sensitive and 92 (29.7%) endocrine resistant. Median follow-up was 20.7 months. Median progression free survival (PFS) was 23.4 months (95%CI: 21.6-NR) in endocrine naive patients, 22.7 months (95%CI: 14.7-NR) in endocrine sensitive, and 13.4 months (95%CI: 10.7–20.8) in endocrine resistant. At 12 months from the initiation of palbociclib, 94.5% of patients were alive. By multivariate analysis, poor prognosis factors for PFS were identified in the endocrine naive/sensitive population: initial ECOG status 2, previous endocrine therapy for ABC, 3 metastatic sites or more. Toxicity profile was similar to previously published data. In a non-selected population of patients with HR + HER2- ABC, the efficacy and safety data are strikingly similar to those previously reported. • Efficacy of palbociclib in advanced breast cancer in real-life is very close to that from the pivotal trials. • Long-term follow-up of patients treated with palbociclib show no cumulative adverse events. [ABSTRACT FROM AUTHOR]

Treatment with CDK4/6 inhibitors and endocrine therapy (CDK4/6i + ET) is a standard for patients with advanced hormone receptor–positive, HER2-negative (HR + HER2–) breast cancer (BC). However, real-world data on the implementation of therapy usage, efficacy, and toxicity have not yet been reported. The PRAEGNANT registry was used to identify advanced HR + HER2– BC patients (n = 1136). The use of chemotherapy, ET, everolimus + ET, and CDK4/6i + ET was analyzed for first-line, second-line, and third-line therapy. Progression-free survival (PFS) and overall survival (OS) were also compared between patients treated with CDK4/6i + ET and ET monotherapy. Also toxicity was assessed. CDK4/6i + ET use increased from 38.5% to 62.7% in the first 2 years after CDK4/6i treatment became available (November 2016). Chemotherapy and ET monotherapy use decreased from 2015 to 2018 from 42.2% to 27.2% and from 53% to 9.5%, respectively. In this early analysis no statistically significant differences were found comparing CDK4/6i + ET and ET monotherapy patients with regard to PFS and OS. Leukopenia was was seen in 11.3% of patients under CDK4/6i + ET and 0.5% under ET monotherapy. In clinical practice, CDK4/6i + ET has been rapidly implemented. A group of patients with a more unfavorable prognosis was possibly treated in the real-world setting than in the reported randomized clinical trials. The available data suggest that longer follow-up times and a larger sample size are required in order to identify differences in survival outcomes. Studies should be supported that investigate whether chemotherapy can be avoided or delayed in this patient population by using CDK4/6i + ET. • CDK4/6i + ET use increased from 39% to 63% after becoming available. • Chemotherapy and ET monotherapy use decreased from 42% to 27% and 53%–10%. • There was no difference between CDK4/6i + ET and ET monotherapy regarding PFS and OS. [ABSTRACT FROM AUTHOR]

There is a lack of prognostic models predicting the overall survival (OS) of advanced breast cancer (ABC) patients in China. Data from the China National Cancer Center database that recorded 4039 patients diagnosed with breast cancer between 1987 and 2019 were extracted and a total of 2263 ABC participants were enrolled in this study, which were further randomized 3:1 and divided into training (n = 1706) and validation (n = 557) groups. The nomogram was built based on independent predictors identified by univariate and multivariate cox regression analyses. The discriminatory and predictive capacities of the nomogram were assessed by Harrell's concordance index (C-index) and calibration plots. Univariate and multivariate analyses found that age, Eastern Cooperative Oncology Group (ECOG) score, T-stage, N-stage, tumor subtype, the presence of distant lymph node (DLN)/liver/brain metastasis, local therapy, efficacy of first-line therapy and metastatic-free interval (MFI) were significantly related to OS (all P < 0.05). These variables were incorporated into a nomogram to predict the 2-year and 3-year OS of ABC patients. The C-indexes of the nomogram were 0.700 (95% confidence interval [CI]: 0.683–0.717) for the training set and 0.686 (95% CI: 0.652–0.719) for the validation set. The calibration curves revealed satisfactory consistency between actual survival and nomogram prediction in both the internal and external validations. The nomogram was capable of stratifying patients into different risk cohorts. We constructed and validated a nomogram that might serve as an efficient tool to provide prognostic prediction for ABC patients and guide the physicians to make personalized treatment decisions. • The nomogram might serve as an efficient tool to provide prognostic prediction for advanced breast cancer patients. • This model could identify low-risk patients who might benefit from aggressive local curative treatment of liver metastasis. • The nomogram suggested that the low-risk triple-negative breast cancer patients demanded more intensive treatments. • External validation from other centers was needed. [ABSTRACT FROM AUTHOR]

Background. The combination of chemotherapy plus anti HER-2 agents is the mainstay of HER-2 positive advanced breast cancer (ABC) therapy. We conducted a phase II trial testing activity and safety of trastuzumab and metronomic capecitabine/cyclophosphamide (HEX) as first-line therapy in HER-2 positive ABC. Methods. Patients at first relapse or with synchronous metastasis were treated with trastuzumab (4 mg/kg, biweekly) plus oral capecitabine (1500 mg/daily) and cyclophosphamide (50 mg/daily). Primary endpoint was objective response rate (ORR), secondary endpoints progression-free survival (PFS), clinical benefit rate (CBR; PR + CR + SD for ≥ 24 weeks) and tolerability. Optimal two-stage design was applied. Results. Sixty patients with measurable ABC, tumors scored as +3 for HER-2 or FISH +, untreated for advanced disease were enrolled. Median age was 62.5 years, visceral metastases were present in most patients (57.9%). Median number of cycles was 16 (range 1–98). ORR was 56.7% (95% CI, 44.1–68.4%), with 5 CR (8.3%) and 29 PR (48.3%). Fifteen patients had SD (25%). The CBR was 78.2%. Nine progressions were observed (15%). Median PFS was 11 months. One year PFS was 47.7%. Median OS was 45.9 months. Worst toxicities were grade 3 hand-foot syndrome in 2 pts (3.3%), grade 3 anaemia in 2 pts (3.3%), grade 2 nausea in 2 pts (3.3%) and grade 3–4 diarrhea in 2 pts (3.3%). Cardiac toxicity grade 1 was reported in 1 pt. Conclusions. Combination of trastuzumab and metronomic oral chemotherapy has clinical activity. The tolerability was excellent and allowed the prolonged delivery of treatment. • Combination of chemotherapy plus anti HER-2 agents is the standard treatment of HER-2 positive breast cancer. • Combination of trastuzumab and metronomic chemotherapy is an alternative therapeutic approach. • Metronomic therapy allows long-term administration of drugs. • Mild toxicity in advanced breast cancer is desirable. [ABSTRACT FROM AUTHOR]

This phase II study evaluated the impact of adding ribociclib to maintenance endocrine therapy (ET) treatment of physicians' choice following the first palliative chemotherapy in pre- and post-menopausal women with hormone receptor positive (HR+)/human epidermal growth factor 2 negative (HER2-) metastatic breast cancer (mBC). The initial randomized study design was later amended into a single-arm study, and all subsequent patients received ribociclib and ET. The primary end point was locally assessed progression-free survival (PFS). Secondary end points included overall survival (OS), clinical benefit rate (CBR), safety, compliance, and quality of life (QoL). A total of 43 patients received ribociclib + ET and 10 patients received ET only. Median PFS was 12.4 months [95% CI 8.7–24.4] for patients who received ribociclib + ET and 4.75 months [95% CI 1.0–10.3] for those who received ET only. Median OS was not reached for patients who received ribociclib + ET, and 28 (65.1%) patients experienced clinical benefit [95% CI 49.1–79.0]. For patients who received ribociclib + ET, grade 3–4 hematological adverse events (AEs) occurred in 25 (58.1%) patients, and grade 3–4 non-hematological AEs occurred in 17 (39.5%) patients. During the study, 15 patients died – 14 of whom due to tumor-related reasons, and one patient due to pneumonia, which was not treatment-related. The results of the AMICA study show a promising efficacy and safety of maintenance treatment with ribociclib added to ET after at least stable disease following the first metastatic chemotherapy in patients with HR+/HER2-mBC. Anti-hormonal Therapy With Ribociclib in HR-positive/HER2- Negative Metastatic Breast Cancer (AMICA), NCT03555877, https://clinicaltrials.gov/ct2/show/NCT03555877. • Ribociclib has the potential to delay disease progression and improve the clinical benefit in patients with HR+/HER2-metastatic breast cancer after palliative chemotherapy. • Treatment tolerability was in line with the known safety profile of ribociclib without new safety concerns. • Most treatment discontinuations occurred due to tumor progression and were not treatment related. • Quality of life was comparable between baseline and treatment end within the study. [ABSTRACT FROM AUTHOR]

Common therapies for HER2-positive advanced breast cancer (ABC) are associated with heterogeneity in prognosis and treatment benefit. Prognostic models of survival outcomes with ado-trastuzumab-emtansine (T-DM1) have not been evaluated. A pre-treatment prognostic model for overall survival (OS) and progression-free survival (PFS) based on clinicopathological factors was developed for HER2-positive ABC patients initiating second-line and later T-DM1 using data from the randomised clinical trials EMILIA and TH3RESA (n = 893). Pre-treatment prognostic groups were identified via recursive partitioning analysis. The most significant OS/PFS pre-treatment risk predictors were metastatic sites count (≤2 versus > 2) and ECOG performance-status (0 versus ≥ 1) (P < 0.05). Based on these two factors, patients can be characterised as one of three prognostic groups (good = 0 factors; intermediate = 1 factor; poor = 2 factors). The prognostic groups were identified as significantly associated with OS (P < 0.001) and PFS (P < 0.001). Median OS for the good, intermediate and poor prognostic groups were 40 (95%CI: 36–48), 25 (23–30) and 16 (14–19) months, respectively, and median PFS was 12 (10–15), 8 (7–9) and 6 (4–7) months. Pre-treatment prognostic groups with significant differences in OS and PFS for HER2-positive ABC patients initiating second-line and later T-DM1 were identified. For HER2-positive ABC patients considering initiating second-line and later T-DM1, the prognostic groups enable more personalized expectations of disease control, survival and absolute treatment benefit. • A prognostic tool for HER2-positive ABC patients initiating T-DM1 therapy. • Prognostic groups were significantly associated with PFS and OS. • Median PFS ranged from 6 to 12 months across the prognostic groups. • Median OS ranged from 16 to 40 months across the prognostic groups. • Provide personalized expectations of disease control and survival. [ABSTRACT FROM AUTHOR]

Abstract Purpose We aimed to assess the implementation and effectiveness of exemestane plus everolimus treatment per hospital type in real-life, shortly after approval of everolimus. Methods Advanced breast cancer patients treated with exemestane plus everolimus in 2012–2014 were included from the SONABRE registry. Progression-free survival (PFS) and a 12-week conditional PFS (post-hoc) were estimated by Kaplan-Meier method. The multivariable Cox proportional hazards model was performed by type of hospital and adjusted for patient, tumour and treatment characteristics. Results We included 122 patients, comprising 48 patients treated in academic (N = 1), 56 in teaching (N = 4), and 18 in non-teaching (N = 2) hospitals. The median PFS was 6.3 months (95% Confidence Interval (CI) 4.0–8.6) overall, and 8.5 months (95% CI 7.7–9.3), 4.2 months (95% CI 2.0–6.3), and 5.5 months (95% CI 4.2–6.7) for the patients treated in academic, teaching and non-teaching hospitals, respectively. The adjusted Hazard Ratio (HR) for PFS-events was 1.5 (95% CI 1.0–2.2) and 1.0 (95% CI 0.5–1.9) respectively for patients treated at teaching and non-teaching hospitals versus the academic hospital. The adjusted HR for 12-week conditional PFS-events was not different between hospital types. In the first 12-week treatment period, treatment was discontinued due to early progression in one out of 48 patients in the academic versus nine out of 74 patients in the non-academic hospitals, confirmed by imaging in one and two patients, respectively. Conclusions In our study, the median PFS was borderline significantly different between hospital types, possibly the result of a different assessment approach in the first 12-week treatment period. Highlights • The real-life overall median progression-free survival (PFS) was 6.3 months. • The median PFS was borderline significantly different between hospital types. • The assessment of progression seemed different in the first 12-week treatment period. • We recommend physicians to broadly share protocols and treatment experience. [ABSTRACT FROM AUTHOR]

Abstract Background The addition of ribociclib (RIB) to letrozole (LET) significantly increases progression free survival for patients with hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). We identified the range of drug costs for which RIB could be considered cost effective from a Chinese perspective. Methods A discrete event simulation model was developed to model the treatment sequences among patients with ABC. Life years (LYs), quality-adjusted LYs (QALYs) and lifetime costs were estimated. Costs were estimated for Chinese health care systems. Three times the per capita gross domestic product (GDP) of China 2016 ($24,360) and three times the per capita GDP of Beijing city 2016 ($53,384) were used as the willingness-to-pay threshold. Probabilistic sensitivity analyses were performed. Results In the base case analysis, RIB + LET provided an incremental survival benefit of 0.631 LYs and 0.451 QALYs. When RIB costs less than $721 or $1170 per 4 weeks, there was a nearly 90% likelihood that the incremental cost-effectiveness ratio for RIB + LET would be less than $24,360 per QALY or $53,384 per QALY, respectively. Conclusion A value-based price for the cost of RIB is $732 or $1170 per 4 weeks for China and Beijing City, respectively. Our study is helpful to inform the multilateral drug price negotiations in China that may be upcoming for RIB. Highlights • Value-based price of ribociclib is $732 per 4 weeks for China. • Value-based price of ribociclib is $1170 per 4 weeks for Beijing city. • The value-based price of ribociclib is helpful to inform the drug price negotiation. [ABSTRACT FROM AUTHOR]

Abstract Metastatic or advanced breast cancer (mBC/ABC) remains incurable despite many different systemic treatment options. Hormone receptor positive (HR+) disease represents the most common subtype in both early and advanced disease. A better understanding of the biology of this BC subtype, in particular regarding potential mechanisms of endocrine resistance, has led to the development of CDK4/6 inhibitors. All three selective CDK4/6 inhibitors, palbociclib, ribociclib and abemaciclib have shown to significantly improve progression-free survival (PFS) when combined to endocrine therapy as first-line treatment for patients with HR+/HER-2 negative ABC, who have progressed on or after adjuvant endocrine therapy. All three of them have also shown an improved PFS as 2nd line therapy for HR+/Her2 negative ABC. Their toxicity profile is favorable, with hematological toxicity (mainly neutropenia) being predominant, followed by diarrhea and fatigue. Quality of life has been maintained in the 1st line setting or improved in the 2nd line setting. Overall survival (OS) has been reported so far only in 2 out of 7 trials as first line therapy and the difference did not reach statistical significance. In this article we review the biology of CDK signaling pathway and its inhibitors, preclinical and clinical data of all three investigated selective CDK4/6 inhibitors and their toxicity. We also discuss how these agents are being included in current international guidelines and future directions for these agents in other subtypes of breast cancer, in both advanced disease and early-stage disease. Highlights • A better understanding of endocrine resistance of HR-positive HER-2-negative ABC, has led to the development of CDK4/6 inhibitors. • Palbociclib, ribociclib and abemaciclib have shown to significantly improve PFS when combined to ET as first or second line treatment for patients with HR+/HER-2 negative ABC. Quality of life of patients seems to be good with low toxicity. Data on OS will be available soon. • Currently, there are no known tissue or blood biomarkers that can predict benefit from CDK4/6 inhibition. Further biomarker analyses are indispensable to better select patients who derive the greatest benefit from CDK4/6 inhibitors, in both early and advanced settings. • There are many unanswered questions in the management of HR+/HER-2 negative ABC, namely what is the best sequencing of all available treatment options, how do combinations of CDK4/6 inhibitors + ET and mTOR inhibitors + ET compare with each other and with chemotherapy. • Improved knowledge of mechanisms of resistance to CDK4/6 inhibitors may in near future help to better tailor subsequent therapy after progression on CDK inhibitors. [ABSTRACT FROM AUTHOR]

Approximately 0.5 million people worldwide die from metastatic breast cancer (mBC) every year. This manuscript provides an overview on the status of mBC in several regions of the world, highlighting the gaps in care, resources, and support available for patients with mBC. Primary research was conducted in 2015 and 2016, comprising four global qualitative and quantitative surveys of approximately 15,000 individuals in 34 countries. Secondary research was conducted using literature reviews of peer-reviewed publications, patient survey reports, and media or online articles. There have been modest improvements in mBC outcomes over the past decade. Patients are not provided with adequate information about mBC. There is a need for open discussion with patients and caregivers about realistic goals; however, physicians are not trained in communicating with patients about their disease. Maintaining patients' quality of life is a crucial goal; however, this has not improved, and in some cases, may have declined in the past decade. Public awareness and understanding of mBC is limited, with damaging consequences for patients and caregivers. Issues affecting employment remain relevant to patients with mBC and their caregivers. Globally, mBC is associated with a substantial economic burden. Relationships with caregivers are crucial to patients with mBC, and caregiver support needs are often overlooked. A strong and united global effort among healthcare professionals, including clinicians, oncologists, pharmaceutical manufacturers, payers, and policy makers, and with advocates, families, and patients, is necessary to improve the outcome and quality of life for patients with mBC. [ABSTRACT FROM AUTHOR]

Since the identification of the HER2 receptor amplification as an adverse prognostic factor that defined a special subtype of metastatic breast cancer, there has been a substantial improvement in survival of patients affected with this disease due to the development of anti-HER2 targeted therapies. The approval of trastuzumab and pertuzumab associated to a taxane in first line and subsequent treatment with the antibody-drug conjugate T-DM1 has certainly contributed to achieve these outcomes. The Tyrosine Kinase Inhibitor lapatinib was also approved in the basis of an improvement in progression free survival, becoming another commonly used treatment in combination with capecitabine. Inevitably, despite these therapeutic advances most patients progress on therapy due to primary or acquired resistance or because of an incorrect HER2 positivity assessment. Hence, it is crucial to correctly categorize HER2 amplified tumors and define mechanisms of resistance to design effective new treatment approaches. In addition, identifying biomarkers of response or resistance permits to tailor the therapeutic options for each patient sparing them from unnecessary toxicity as well as improving their outcomes. The aim of this review is to examine new strategies in development to treat HER2-positive metastatic breast cancer referring to the mechanisms of action of new drugs and new combinations including results reported so far. [ABSTRACT FROM AUTHOR]

Objectives The double-blind, phase III CONFIRM study ( NCT00099437 ) evaluated fulvestrant 500 mg vs fulvestrant 250 mg in postmenopausal women with hormone receptor-positive locally advanced/metastatic breast cancer (LA/MBC). This post-hoc analysis investigated the efficacy and safety of fulvestrant given either first-line or second-line for advanced disease. Materials & methods Progression-free survival (PFS) and overall survival (OS) with fulvestrant 500 mg vs fulvestrant 250 mg was evaluated using unadjusted log-rank tests in patients treated in the first- (progression during or within 12 months after completing adjuvant endocrine therapy; n = 387) and second-line (following endocrine therapy for LA/MBC; n = 343) settings. Results First-line fulvestrant 500 mg significantly prolonged PFS vs fulvestrant 250 mg (median PFS 5.6 vs 4.2 months; hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.64–1.00; p = .047). Median PFS was numerically greater with second-line fulvestrant 500 mg vs fulvestrant 250 mg (7.9 vs 6.3 months; HR 0.80; 95% CI 0.64–1.02; p = .068). At data cut-off (75.5% maturity), median OS with first-line fulvestrant 500 mg was 23.2 vs 22.1 months with fulvestrant 250 mg (HR 0.87; 95% CI 0.70–1.10; p = .251), and 29.2 vs 22.8 months, respectively, in the second-line (HR 0.75; 95% CI 0.58–0.96; p = .020). The safety profile was broadly comparable between dose groups and across treatment lines, and consistent with the overall patient population. Conclusion The superiority of fulvestrant 500 mg over fulvestrant 250 mg in patients with LA/MBC in CONFIRM was consistent in both the first- and second-line settings for PFS, and numerically greater in both settings for OS. [ABSTRACT FROM AUTHOR]

Purpose This study describes comprehensive data from a breast cancer registry concerning the use of endocrine treatment (ET) and chemotherapy in the first, second and higher therapy lines in hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC). Methods The PRAEGNANT study is a real-time registry for patients with MBC. Therapies were categorized into the following categories: chemotherapy, aromatase inhibitor (AI), tamoxifen, fulvestrant, or everolimus plus ET and reported for first, second and third line or higher therapy use. Also treatment sequences for the first, second and third therapy line were analyzed. Results This analysis includes 958 patients with HR positive, HER2 negative MBC. 42.7% were treated with a chemotherapy in the first therapy line compared to 45.9% receiving an ET. A total of 25.9% were treated with everolimus plus anti-hormone therapy in any therapy line. 34.1% were treated with fulvestrant as single agent therapy. Analyzing therapy sequences, the administration of three different chemotherapies in a row was the most frequently used pattern. Conclusions This analysis shows that across all three first therapy lines chemotherapy is a dominant therapy for HR positive, HER2 negative MBC patients. Education about the efficacy of ET might help to increase its use and decrease the possible burden of chemotherapy related toxicities. [ABSTRACT FROM AUTHOR]

Objectives Improved progression-free survival is considered as treatment goal for patients with metastatic breast cancer (MBC) since it is assumed to delay or prevent deterioration of quality of life. Aim of our analysis was to examine the influence of disease progression on health-related quality of life (HRQoL). Materials and methods The PRAEGNANT study comprises a real-life registry for patients with MBC. HRQoL was assessed with the EORTC-QLQ-C30 Version 3.0 questionnaire at study entry and every 3 months thereafter. The primary endpoint was minimally important deterioration (MID) in global HRQoL score by ≥ five points between baseline and any follow-up assessment. A logistic regression model was built with MID (yes/no) at a follow-up timepoint as outcome variable and several covariates as predictors. Results In total, 329 patients were included in this analysis, with disease progression in 63 patients. Concerning the primary study aim, progression status predicted MID of global HRQoL status in addition to the other covariates. The adjusted odds ratio for the effect of progression status on MID was 2.22 (95% CI: 1.04 - 4.73). Comparisons of mean differences of QoL domains/scales yielded no differences. Conclusions We provide evidence that disease progression in patients with metastatic breast cancer in a real-world registry has a significant negative impact on HRQoL as measured by MID of HRQoL. This study emphasizes the relevance of avoiding progression and prolonging PFS to maintain QoL. [ABSTRACT FROM AUTHOR]