AMEERA-3: Randomized Phase II Study of Amcenestrant (Oral Selective Estrogen Receptor Degrader) Versus Standard Endocrine Monotherapy in Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer.

PURPOSE: Amcenestrant (oral selective estrogen receptor degrader) demonstrated promising safety and efficacy in earlier clinical studies for endocrine-resistant, estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2-) advanced breast cancer (aBC). PATIENTS AND METHODS: In AMEERA-3 (ClinicalTrials.gov identifier: NCT04059484), an open-label, worldwide phase II trial, patients with ER+/HER2- aBC who progressed in the (neo)adjuvant or advanced settings after not more than two previous lines of endocrine therapy (ET) were randomly assigned 1:1 to amcenestrant or single-agent endocrine treatment of physician's choice (TPC), stratified by the presence/absence of visceral metastases, previous/no treatment with cyclin-dependent kinase 4/6 inhibitor, and Eastern Cooperative Oncology Group performance status (0/1). The primary end point was progression-free survival (PFS) by independent central review, compared using a stratified log-rank test (one-sided type I error rate of 2.5%). RESULTS: Between October 22, 2019, and February 15, 2021, 290 patients were randomly assigned to amcenestrant (n = 143) or TPC (n = 147). PFS was numerically similar between amcenestrant and TPC (median PFS [mPFS], 3.6 v 3.7 months; stratified hazard ratio [HR], 1.051 [95% CI, 0.789 to 1.4]; one-sided P = .643). Among patients with baseline mutated ESR1; (n = 120 of 280), amcenestrant numerically prolonged PFS versus TPC (mPFS, 3.7 v 2.0 months; stratified HR, 0.9 [95% CI, 0.565 to 1.435]). Overall survival data were immature but numerically similar between groups (HR, 0.913; 95% CI, 0.595 to 1.403). In amcenestrant versus TPC groups, treatment-emergent adverse events (any grade) occurred in 82.5% versus 76.2% of patients and grade ≥3 events occurred in 21.7% versus 15.6%. CONCLUSION: AMEERA-3 did not meet its primary objective of improved PFS with amcenestrant versus TPC although a numerical improvement in PFS was observed in patients with baseline ESR1 mutation. Efficacy and safety with amcenestrant were consistent with the standard of care for second-/third-line ET for ER+/HER2- aBC.

Adjuvant Dose Dense Chemotherapy in Patients With Obesity: Short-Term Toxicities and Breast Cancer Outcome.

BACKGROUND: Dose dense adjuvant chemotherapy is associated with improved outcomes in breast cancer compared to standard dosing. Despite current guidelines recommending that chemotherapy is dosed according to actual body weight, reviews have shown patients with obesity often receive a capped chemotherapy dose. The latter is commonly undertaken as clinicians have concerns that adverse events are more frequent if full doses are administered. This study assessed surgical, radiotherapy and chemotherapy related adverse events between patients with and without obesity receiving dose dense adjuvant chemotherapy for breast cancer. MATERIALS AND METHODS: A retrospective review of prospective collected data for patients receiving adjuvant chemotherapy from 30 April 2018 from a single institution was analyzed. Data collected included demographic data, height, weight, pathological information, comorbidities, surgical, radiotherapy chemotherapy treatment, and toxicity. Primary outcomes were surgical complications at 30 days, radiotherapy skin toxicity at 30 days and chemotherapy side-effects. Secondary outcomes were rates of recurrence and time to recurrence. RESULTS: A total of 280 patients were included in the analysis: 55 obese and 225 nonobese. Obese status was associated with higher rates of grade >2 skin toxicity and this difference was significant after adjusting for age, comorbidity and radiotherapy field (P = .017). Obese status was not associated with higher rates of surgical or chemotherapy related adverse events. All patients regardless of obese status received adequate dose intensity with similar rates of recurrence and time to recurrence. CONCLUSION: Patients with obesity who receive dose dense adjuvant chemotherapy do not experience higher rates of surgical or chemotherapy related adverse events although they do experience higher rates of grade >2 radiotherapy related skin toxicity. This supports the use of dose dense chemotherapy being based on actual body weight in patients with obesity.

Potential therapeutic role for pigment epithelium-derived factor in post-menopausal breast cancer bone metastasis.

OBJECTIVES: This review discusses key oestrogens associated with the circulating pre- and post-menopausal milieu and how they may impact intratumoral oestrogen levels and breast cancer (BC) metastasis. It also identifies critical steps in BC metastasis to bone from the viewpoint of pigment epithelium-derived factor (PEDF) function, and discusses the role of several associated pro-metastatic biomarkers in BC bone metastasis. KEY FINDINGS: PEDF is regulated by oestrogen in a number of oestrogen-sensitive tissues. Changes in circulating oestrogen levels associated with menopause may enhance the growth of BC bone metastases, leading to the establishment of a pre-metastatic niche. The establishment of such a pre-metastatic niche is driven by several key mediators, with pro-osteoclastic and pro-metastatic function which are upregulated by BC cells. These mediators appear to be regulated by oestrogen, as well as differentially affected by menopausal status. PEDF interacts with several pro-metastatic, pro-osteoclastic biomarkers, including C-X-C motif chemokine receptor 4 (CXCR4) and nuclear factor kappa B (NFκB) in BC bone metastasis. CONCLUSION: Mediators such as CXCR4 and MT1-MMP underpin the ability of PEDF to function as an antimetastatic in other cancers such as osteosarcoma, highlighting the possibility that this serpin could be used as a therapeutic against BC metastasis in future.

Overall survival with neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): A randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: ExteNET showed that neratinib, an irreversible pan-HER tyrosine kinase inhibitor, given for 1 year after trastuzumab-based therapy significantly improved invasive disease-free survival in women with early-stage HER2-positive breast cancer. We report the final analysis of overall survival in ExteNET. METHODS: In this international, randomised, double-blind, placebo-controlled, phase 3 trial, women aged 18 years or older with stage 1-3c (amended to stage 2-3c) HER2-positive breast cancer who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab were eligible. Patients were randomly assigned to oral neratinib 240 mg/day or placebo for 1 year. Randomisation was stratified according to hormone receptor (HR) status (HR-positive vs. HR-negative), nodal status (0, 1-3 or 4+), and trastuzumab regimen (sequentially vs. concurrently with chemotherapy). Overall survival was analysed by intention to treat. ExteNET is registered (Clinicaltrials.gov: NCT00878709) and is complete. RESULTS: Between July 9, 2009, and October 24, 2011, 2840 women received neratinib (n = 1420) or placebo (n = 1420). After a median follow-up of 8.1 (IQR, 7.0-8.8) years, 127 patients (8.9%) in the neratinib group and 137 patients (9.6%) in the placebo group in the intention-to-treat population had died. Eight-year overall survival rates were 90.1% (95% CI 88.3-91.6) with neratinib and 90.2% (95% CI 88.4-91.7) with placebo (stratified hazard ratio 0.95; 95% CI 0.75-1.21; p = 0.6914). CONCLUSIONS: Overall survival in the extended adjuvant setting was comparable for neratinib and placebo after a median follow-up of 8.1 years in women with early-stage HER2-positive breast cancer.

Prognostic role of immune environment in luminal B early breast cancer.

The importance of the immune microenvironment in triple negative and HER2-amplified breast cancer (BC) is well-established; less is known about the immune environment in luminal breast cancers. We aimed to assess for the impact of immune biomarkers on BC outcome in a group of luminal B patients with archived tissue and annotated clinical information. Patients with early breast cancer (EBC) treated in a single institution over a 14-year period, with prospectively collected data were included. Luminal B EBC patients were identified and defined into three cohorts: A: grade 2 or 3, ER & PR positive, HER2-negative; B: Any grade, ER positive, PR and HER2-negative (Ki67 ≥ 14% in cohorts A & B); and C: Any grade, ER or PR positive, HER2-positive. Within each cohort, patients with a relapsed BC event (R) were compared on a 1:1 basis with a control patient (C) who remained disease-free, balanced for key characteristics in an effort to balance the contribution of each clinical group to outcome. Archival breast, involved and uninvolved axillary nodes were assessed by immunohistochemistry for biomarkers identifying effector and suppressor immune cells, and compared between R and C. In total, 120 patients were included (80, 22, and 18 patients in cohorts A, B, and C, respectively). R were 1.5 years older (p = 0.016), with all other characteristics being balanced. Overall, there were no statistically significant differences in immune biomarkers in breast or nodal tissue of R and C. However, there was a trend toward higher levels of TILs in breast tumors of C, while GAL-9 was consistently expressed on lymphocytes and tumor cells in all breast and nodes of C and was absent from all tissues of R. These trends in checkpoint molecule expression deserve further research.

Final findings from the CONTROL trial: Strategies to reduce the incidence and severity of neratinib-associated diarrhea in patients with HER2-positive early-stage breast cancer.

BACKGROUND: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for HER2-positive early-stage and metastatic breast cancer. Diarrhea is the most frequent side effect and the most common reason for early discontinuation. The phase II CONTROL trial investigated antidiarrheal prophylaxis or neratinib dose escalation (DE) for prevention of diarrhea. We present complete study results including final data for two DE strategies. METHODS: Patients who completed trastuzumab-based adjuvant therapy received neratinib 240 mg/day for 1 year. Early cohorts investigated mandatory prophylaxis with loperamide, then additional budesonide or colestipol. Final cohorts assessed neratinib DE over the first 2 (DE1) or 4 weeks (DE2). The primary endpoint was incidence of grade ≥3 diarrhea. Health-related quality of life (HRQoL) was assessed using FACT-B and EQ-5D-5L. RESULTS: 563 patients were enrolled into six cohorts. All strategies reduced grade ≥3 diarrhea with the lowest incidence in DE1 (DE1 13%; colestipol + loperamide [CL] 21%, DE2 27%; budesonide + loperamide [BL] 28%; loperamide [L] 31%; colestipol + loperamide as needed [CL-PRN] 33%). Diarrhea-related discontinuations occurred early and were lowest in DE1 (DE1 3%; CL 4%; DE2 6%; CL-PRN 8%; BL 11%; L 20%). More patients stayed on neratinib for the prescribed period versus historical controls. Prior pertuzumab use did not affect rates of grade ≥3 diarrhea, diarrhea-related discontinuations, or treatment duration. Early transient reductions in HRQoL scores were observed. CONCLUSIONS: These complete results from CONTROL show improved neratinib tolerability with proactive management at the start of therapy. Two-week neratinib DE with loperamide as needed was particularly effective. GOV REGISTRATION NUMBER: NCT02400476.

Pigment epithelium-derived factor downregulation in oestrogen receptor positive breast cancer bone metastases is associated with menopause.

Pigment epithelium-derived factor (PEDF) has a critical role in bone development and anti-tumour function in breast cancer (BC). As the expression and role of PEDF in BC bone metastases is unknown, we aimed to characterise PEDF in primary and metastatic BC. Subcellular PEDF localisation was semi-quantitatively analysed via immunohistochemistry in patient-matched, archived formalin-fixed paraffin-embedded primary BC and liver, lung, and decalcified bone metastases specimens. PEDF localisation was evaluated in 23 metastatic BC patients diagnosed with ER+, human epidermal growth factor receptor-2 (HER2) negative BC or TNBC. Cytoplasmic (p = 0.019) and membrane (p = 0.048) PEDF was lower in bone metastases compared to primary ER+/HER2- BC. In contrast, nuclear PEDF scores were higher in metastases compared to primary TNBC (p = 0.027), and increased membrane PEDF in metastatic tissue had improved disease-free interval (p = 0.016). Nuclear PEDF was decreased in bone metastases compared to primary ER+//HER2- BC in post-menopausal patients (p = 0.029). These novel findings indicate PEDF plays a role in clinical BC metastasis. Significantly lower PEDF levels in the post-menopausal compared to pre-menopausal setting suggests future PEDF research may have greater clinical importance in the post-menopausal ER+/HER2- BC population.

NFκB-Mediated Mechanisms Drive PEDF Expression and Function in Pre- and Post-Menopausal Oestrogen Levels in Breast Cancer.

Pigment epithelium-derived factor (PEDF) protein regulates normal bone, with anti-tumour roles in bone and breast cancer (BC). Pre- and post-menopausal oestrogen levels may regulate PEDF expression and function in BC, though the mechanisms behind this remain unknown. In this study, in vitro models simulating pre- and post-menopausal bone microenvironments were used to evaluate if PEDF regulates pro-metastatic biomarker expression and downstream functional effects on BC cells. PEDF treatment reduced phosphorylated-nuclear factor-κB p65 subunit (p-NFκB-p65), tumour necrosis factor-α (TNFα), C-X-C chemokine receptor type-4 (CXCR4), and urokinase plasminogen activator receptor (uPAR) in oestrogen receptor (ER)+/human epidermal growth factor receptor-2 (HER2)- BC cells under post-menopausal oestrogen conditions. In triple negative BC (TNBC) cells, PEDF treatment reduced pNFκB-p65 and uPAR expression under pre-menopausal oestrogen conditions. A potential reciprocal regulatory axis between p-NFκB-65 and PEDF in BC was identified, which was BC subtype-specific and differentially regulated by menopausal oestrogen conditions. The effects of PEDF treatment and NFκB inhibition on BC cell function under menopausal conditions were also compared. PEDF treatment exhibited superior anti-viability effects, while combined PEDF and NFκB-p65 inhibitor treatment was superior in reducing BC cell colony formation in a subtype-specific manner. Lastly, immunohistochemical evaluation of p-NFκB-p65 and PEDF expression in human BC and bone metastases specimens revealed an inverse correlation between nuclear PEDF and NFκB expression in bone metastases. We propose that menopausal status is associated with a PEDF/NFκB reciprocal regulatory axis, which drives PEDF expression and anti-metastatic function in a subtype-specific manner. Altogether, our findings identify pre-menopausal TNBC and post-menopausal ER+/HER2- BC patients as target populations for future PEDF research.

Quality-Adjusted Survival with Ribociclib Plus Fulvestrant Versus Placebo Plus Fulvestrant in Postmenopausal Women with HR±HER2- Advanced Breast Cancer in the MONALEESA-3 Trial.

BACKGROUND: MONALEESA-3 demonstrated an overall survival (OS) benefit for ribociclib plus fulvestrant (R+F) in postmenopausal women with hormone receptor (HR) positive, HER2 negative advanced breast cancer (ABC). This study estimated quality-adjusted (QA) survival outcomes for patients receiving R+F vs. placebo (P)+F in MONALEESA-3. METHODS: Kaplan-Meier OS was partitioned into health states: (1) toxicity (TOX)=time spent with grade 3 -4 adverse events before progression (DP); (2) progression (PROG)=time between DP and death; and (3) time without symptoms or toxicity (TWiST)=time not in TOX or PROG. QA time was calculated by combining estimated mean time in each health state with treatment-group specific health-state utility values estimated using EQ-5D-5L questionnaire. Outcomes included QA progression-free survival (QAPFS), QAOS, and QA TWiST (Q-TWiST). Q-TWiST was calculated with health-state utility values for TOX and PROG defined relative to TWiST. RESULTS: Mean PFS and OS were significantly greater with R+F vs. P+F (difference 0.56 and 0.19 years). Mean time in TOX and TWiST were greater with R+F; mean time in PROG was greater with P+F. QAPFS was 0.45 years (95% CI 0.27 -0.63) greater with R+F than P+F (P <.001). QAOS was numerically greater with R+F vs. P+F (0.16 years, 95% CI 0.07 -0.45, P = .0569). Q-TWiST was 0.23 years greater with R+F (95% CI 0.07 -0.45, P = .0069). In a sensitivity analysis using an estimate of disutility for PROG, the difference in QAOS was 0.23 years (95% CI 0.08 -0.41, P = .0022). CONCLUSION: R+F in postmenopausal women with HR+/HER2- ABC improves QAPFS, resulting in clinically important improvements in Q-TWiST and may improve QAOS.

A Randomized Phase II Study of Anti-CSF1 Monoclonal Antibody Lacnotuzumab (MCS110) Combined with Gemcitabine and Carboplatin in Advanced Triple-Negative Breast Cancer.

PURPOSE: This phase II study determined the efficacy of lacnotuzumab added to gemcitabine plus carboplatin (gem-carbo) in patients with advanced triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Female patients with advanced TNBC, with high levels of tumor-associated macrophages not amenable to curative treatment by surgery or radiotherapy were enrolled. Lacnotuzumab was dosed at 10 mg/kg every 3 weeks, ± a dose on cycle 1, day 8. Gemcitabine (1,000 mg/m2) and carboplatin (dose in mg calculated by area under the curve [mg/mL/min] × (glomerular filtration rate [mL/min] + 25 [mL/min]) were dosed every 3 weeks. Treatment continued until unacceptable toxicity, disease progression, or discontinuation by physician/patient. RESULTS: Patients received lacnotuzumab + gem-carbo (n = 34) or gem-carbo (n = 15). Enrollment was halted due to recruitment challenges owing to rapid evolution of the therapeutic landscape; formal hypothesis testing of the primary endpoint was therefore not performed. Median progression-free survival was 5.6 months [90% confidence interval (CI), 4.47-8.64] in the lacnotuzumab + gem-carbo arm and 5.5 months (90% CI, 3.45-7.46) in the gem-carbo arm. Hematologic adverse events were common in both treatment arms; however, patients treated with lacnotuzumab experienced more frequent aspartate aminotransferase, alanine aminotransferase, and creatine kinase elevations. Pharmacokinetic results showed that free lacnotuzumab at 10 mg/kg exhibited a typical IgG pharmacokinetic profile and target engagement of circulating colony-stimulating factor 1 ligand. CONCLUSIONS: Despite successful target engagement and anticipated pharmacokinetic profile, lacnotuzumab + gem-carbo showed comparable antitumor activity to gem-carbo alone, with slightly poorer tolerability. However, the data presented in this article would be informative for future studies testing agents targeting the CSF1-CSF1 receptor pathway in TNBC.

Drug induced vitiligo-like depigmentation from a CDK 4/6 inhibitor.

Ribociclib is an inhibitor of cyclin-dependent kinases 4 and 6 (CDK 4/6) that is used in combination with an aromatase inhibitor in the first-line setting for advanced or metastatic hormone receptor positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. We report two cases of drug-induced vitiligo-like depigmentation (DI-VLD) associated with ribociclib. The awareness of this side effect is important given the increasing use of this drug and others with a similar mechanism of action.

Incorporation of eribulin in the systemic treatment of metastatic breast cancer patients in Australia.

PURPOSE: Review of utilization and efficacy of eribulin in Australian metastatic breast cancer (MBC) patients. METHODS: Retrospective review of consecutive MBC patients treated with eribulin in tertiary Australian BC centers. Key inclusion criteria included eribulin administration in nonclinical trial setting from October 2014 onwards, known duration of MBC systemic treatments administered and known follow-up date after eribulin. Cox regression model was used to assess survival. RESULTS: Study population comprised 266 patients from eight centers treated between October 2014 and May 2018. Median age at time of MBC diagnosis was 54 years with 18% of patients having de novo MBC. Seventy-six percent had hormone receptor positive (HRp) disease, 19% triple negative (TN) and 5% HER2-positive. CNS involvement was present in 36% of patients. Eribulin was most frequently given as third-line chemotherapy (36%), with no prior anthracycline exposure in 14% of total population. Eribulin was given more frequently as ≤third-line chemotherapy than > third-line in patients with TN disease, ≥ two metastatic sites or CNS disease. Median overall survival (OS) from eribulin administration was 9.2 (95% CI [8.0, 10.3]) months. CONCLUSION: Similar efficacy was demonstrated for eribulin when given in the first-line to beyond the fifth line of chemotherapy in all subtypes of MBC.

Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03).

PURPOSE: Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, the potential value of adding palbociclib to endocrine therapy for hormone receptor-positive breast cancer has not been confirmed. PATIENTS AND METHODS: In the prospective, randomized, phase III PALLAS trial, patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 years). The primary end point of the study was invasive disease-free survival (iDFS); secondary end points were invasive breast cancer-free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival. RESULTS: Among 5,796 patients enrolled at 406 centers in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups (iDFS at 4 years: 84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant differences were observed for secondary time-to-event end points, and subgroup analyses did not show any differences by subgroup. There were no new safety signals for palbociclib in this trial. CONCLUSION: At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor-positive breast cancer.

BreastSurgANZ members recommendations for adjuvant systemic treatment and patient compliance in Australian breast cancer patients.

BACKGROUND: We aimed to identify compliance with systemic treatment recommendations in early breast cancer (EBC) patients managed by Australian BreastSurgANZ members. METHODS: A retrospective analysis of patients diagnosed with EBC included in BreastSurgANZ prospective database from January 2002 to December 2016 was conducted. Data was available on patients with BC treated by over 350 surgeons across the six states and two territories of Australia. RESULTS: Over the 15 year period, 102 660 EBC episodes were recorded in 99 800 patients. As a group, the five key performance indicators (KPIs) set by the BreastSurgANZ relating to systemic treatment were achieved. Overall, patients were compliant with systemic treatment recommendations with 89.1% of patients receiving treatment in accordance with recommendations from their treating surgeon. The highest rate of non-compliance with systemic treatment was for endocrine therapy (11.9%). Of the 2368 patients who did not proceed with the recommended endocrine treatment, 1284 (54%) patients did so because of patient refusal. Failure to receive chemotherapy was associated with older age (aOR 1.02; p < 0.001), patients living in regional areas (aOR 1.23; p = 0.001) and those with node negative disease (aOR 0.97; p = 0.003). CONCLUSIONS: The majority of Australian patients with EBC are being recommended for adjuvant systemic therapy in accordance with BreastSurgANZ KPI's. Treatment compliance was very high. This finding emphasises the importance of prospective data collection and auditing of established KPIs by surgeons, in areas other than direct surgical outcomes. Further research into the reasons why patients refuse treatment is needed.

Bone Health Outcomes from the International, Multicenter, Randomized, Phase 3, Placebo-Controlled D-CARE Study Assessing Adjuvant Denosumab in Early Breast Cancer.

INTRODUCTION: D-CARE, an international, phase 3, randomized, double-blind, placebo-controlled study in women with early-stage breast cancer at high risk of disease recurrence, failed to meet its primary endpoint-improvement in bone metastasis-free survival (BMFS) with adjuvant denosumab vs placebo injections. As a result of the limitations of assessing BMFS, which includes relapse in bone with and without extraskeletal recurrences and deaths from any cause, the prespecified exploratory bone endpoints' analysis may provide a more clinically meaningful effect of denosumab in this disease setting. METHODS: The study enrolled women (aged ≥ 18 years) with histologically confirmed stage II/III breast cancer. Patients treated with adjuvant/neoadjuvant chemotherapy meeting inclusion criteria were randomly assigned 1:1 to receive either denosumab (120 mg) or placebo subcutaneously every 3-4 weeks for about 6 months and then every 3 months for a total treatment duration of 5 years. Five prespecified exploratory bone endpoints and post hoc subgroup analysis based on age (< 50 and ≥ 50 years) and menopause status (premenopausal and postmenopausal) were evaluated. RESULTS: Overall, 4509 women with early-stage breast cancer were assigned to receive denosumab (N = 2256) or placebo (N = 2253). The baseline demographics and clinical characteristics were comparable between the two arms. The hazard ratio (HR) for time to first bone metastasis was 0.82 (95% CI 0.66-1.02; p = 0.068), with HRs of 0.70 (95% CI 0.52-0.94; p = 0.018) for patients < 50 years old and 0.74 (95% CI 0.55-0.98; p = 0.038) for premenopausal patients, favoring the denosumab group. The HRs for time to first on-study fracture and time to first on-study skeletal-related event were 0.76 (95% CI 0.63-0.92; p = 0.004) and 0.52 (95% CI 0.35-0.78; p = 0.001), respectively, again favoring the denosumab group. CONCLUSION: The exploratory bone endpoints indicate the benefits of denosumab treatment in patients with high-risk early breast cancer, supporting the expected bone health benefits contributed by denosumab. TRIAL REGISTRATION NUMBER: NCT01077154.

Safety and impact of dose reductions on efficacy in the randomised MONALEESA-2, -3 and -7 trials in hormone receptor-positive, HER2-negative advanced breast cancer.

BACKGROUND: This pooled analysis of MONALEESA trials evaluated the safety of ribociclib plus endocrine therapy (RIB + ET) with a focus on dose reductions in first-line patients. METHODS: In the dose reduction analysis, data were pooled from MONALEESA-2 (all patients), MONALEESA-3 (patients receiving treatment as first-line ET) and MONALEESA-7 (patients receiving combination therapy with an NSAI as initial ET). Efficacy was analysed by ribociclib relative dose intensity (DI). Safety was analysed in all patients in the trials (except those receiving tamoxifen in MONALEESA-7) and those with/without ≥1 ribociclib dose reduction. RESULTS: Of 818 women who received first-line RIB + ET, 41.8% required ≥1 dose reduction due to AEs (most commonly, neutropenia). Median RIB relative DI in patients without and with dose reductions was 99.3% and 65.6% in MONALEESA-2, 98.4% and 67.8% in MONALEESA-3 and 98·0% and 66·3% in MONALEESA-7. Median PFS was 24.8, 24.9 and 29.6 months for patients who received ≤71% (30th percentile), 72-96% (60th percentile) and 97-100% (90th percentile) RIB relative DI, respectively. No new safety signals emerged in the pooled safety analysis. CONCLUSIONS: This analysis provides reassuring data showing that the clinical benefit of RIB is preserved when dose modifications are undertaken to manage AEs. TRIAL REGISTRATION: MONALEESA-2 (NCT01958021) first posted October 8, 2013; MONALEESA-3 (NCT02422615) first posted April 21, 2015; MONALEESA-7 (NCT02278120) first posted October 29, 2014.

Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study.

BACKGROUND: Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer. METHODS: PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II-III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1-21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). FINDINGS: Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9-29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2-90·6) for palbociclib plus endocrine therapy and 88·5% (85·8-90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76-1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3-4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths. INTERPRETATION: At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing. FUNDING: Pfizer.

Derived Neutrophil-to-Lymphocyte Ratio Predicts Pathological Complete Response to Neoadjuvant Chemotherapy in Breast Cancer.

BACKGROUND: Derived neutrophil-to-lymphocyte ratio (dNLR) is a biomarker associated with clinical outcome in breast cancer (BC). We analyzed the association of dNLR with pathological complete response (pCR) in triple-negative BC (TNBC) patients receiving neoadjuvant chemotherapy (CT). METHODS: This is a retrospective analysis of two randomized studies involving early stage/locally advanced TNBC patients receiving anthracycline/taxane-based CT+/-carboplatin (GEICAM/2006-03) or nab-paclitaxel/paclitaxel followed by anthracycline regimen (ETNA). dNLR was calculated as the ratio of neutrophils to the difference between total leukocytes and neutrophils in peripheral blood before CT (baseline) and at the end of treatment (EOT). Logistic regression analyses were used to explore dNLR association with pCR. RESULTS: In total, 308 TNBC patients were analyzed, 216 from ETNA and 92 from GEICAM/2006-03. Baseline median dNLR was 1.61 (interquartile range (IQR): 1.25-2.04) and at EOT 1.53 (IQR: 0.96-2.22). Baseline dNLR showed positive correlation with increased tumor size (p-value = 1e-04). High baseline dNLR, as continuous variable or using median cutoff, was associated with lower likelihood of pCR in univariate analysis. High EOT dNLR as continuous variable or using quartiles was also associated with lower pCR rate in uni- and multivariate analyses. CONCLUSIONS: High baseline and EOT dNLR correlates with lower benefit from neoadjuvant CT in TNBC.