Palbociclib with Fulvestrant or Letrozole in Endocrine-Sensitive Patients with HR-Positive/HER2-Negative Advanced Breast Cancer: A Detailed Safety Analysis of the Randomized PARSIFAL Trial.

BACKGROUND: Palbociclib has gained a central role in the treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Despite its manageable toxicity profile, venous thromboembolism (VTE) or interstitial lung disease (ILD)/pneumonitis may infrequently occur. Therefore, we provide a comprehensive summary of the safety and tolerability of the combination of endocrine therapy and palbociclib among patients included in the randomized phase 2 PARSIFAL study. MATERIALS AND METHODS: Patients with endocrine-sensitive HR+/HER2- ABC and no prior therapy in an advanced setting (n = 486) were randomly assigned 1:1 to receive fulvestrant-palbociclib (FP) or letrozole-palbociclib (LP). Laboratory tests and the incidence of adverse events (AEs) were recorded at baseline and day 1 of each cycle. Progression-free survival (PFS) was estimated for patients with and without VTE. RESULTS: A total of 483 patients were analyzed. Neutropenia, leukopenia, anemia, asthenia, arthralgia, fatigue, and diarrhea were the most frequent AEs in both groups. Febrile neutropenia occurred in 3 (1.2%) patients of the FP group and in 1 (0.4%) patient in the LP group. Six (2.5%; 0.4% grade 3) patients in the FP group and 6 patients (2.5%; 0.4% grade 3) in the LP group experienced ILD/pneumonitis. Pulmonary embolism was reported in 12 (5.0%) patients in the FP group and 6 (2.5%) patients in the LP group. Advanced age at baseline was the only factor significantly associated with an increased risk of pulmonary embolism (P < .01). CONCLUSION: The PARSIFAL data confirmed the favorable safety profile of both palbociclib regimens. VTE and ILD/pneumonitis were occasionally reported, and their early detection allowed patients to continue treatment effectively without detriment to efficacy. CLINICALTRIALS.GOV IDENTIFIER: NCT02491983; https://clinicaltrials.gov/ct2/show/NCT02491983).

SOLTI-1904 ACROPOLI TRIAL: efficacy of spartalizumab monotherapy across tumor-types expressing high levels of PD1 mRNA.

Improved selection of cancer patients who are most likely to respond to immune checkpoint inhibitors remains an unmet clinical need. Recently, a positive correlation between levels of PD1 mRNA and clinical outcome in response to PD1 blockade across diverse tumor histologies has been confirmed in several datasets. ACROPOLI is a parallel cohort, non-randomized, phase II study that aims to evaluate the efficacy of the anti-PD1 immune checkpoint inhibitor spartalizumab as monotherapy in metastatic patients with solid tumors that express high levels of PD1 (cohort 1; n = 111). An additional cohort of 30 patients with tumors expressing low levels of PD1, where PD1/PD-L1 antibodies in monotherapy are standard treatment, will also be included (cohort 2). Primary end point is overall response rate in cohort 1. Trial registration number: NCT04802876 (ClinicalTrials.gov).

Trajectories of alcohol consumption during life and the risk of developing breast cancer.

BACKGROUND: Whether there are lifetime points of greater sensitivity to the deleterious effects of alcohol intake on the breasts remains inconclusive. OBJECTIVE: To compare the influence of distinctive trajectories of alcohol consumption throughout a woman's life on development of breast cancer (BC). METHODS: 1278 confirmed invasive BC cases and matched (by age and residence) controls from the Epi-GEICAM study (Spain) were used. The novel group-based trajectory modelling was used to identify different alcohol consumption trajectories throughout women's lifetime. RESULTS: Four alcohol trajectories were identified. The first comprised women (45%) with low alcohol consumption (<5 g/day) throughout their life. The second included those (33%) who gradually moved from a low alcohol consumption in adolescence to a moderate in adulthood (5 to <15 g/day), never having a high consumption; and oppositely, women in the third trajectory (16%) moved from moderate consumption in adolescence, to a lower consumption in adulthood. Women in the fourth (6%) moved from a moderate alcohol consumption in adolescence to the highest consumption in adulthood (≥15 g/day), never having a low alcohol consumption. Comparing with the first trajectory, the fourth doubled BC risk (OR 2.19; 95% CI 1.27, 3.77), followed by the third (OR 1.44; 0.96, 2.16) and ultimately by the second trajectory (OR 1.17; 0.86, 1.58). The magnitude of BC risk was greater in postmenopausal women, especially in those with underweight or normal weight. When alcohol consumption was independently examined at each life stage, ≥15 g/day of alcohol consumption in adolescence was strongly associated with BC risk followed by consumption in adulthood. CONCLUSIONS: The greater the alcohol consumption accumulated throughout life, the greater the risk of BC, especially in postmenopausal women. Alcohol consumption during adolescence may particularly influence BC risk.

Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer (CORALLEEN): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: In hormone receptor-positive, HER2-negative early stage breast cancer, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition in combination with endocrine therapy could represent an alternative to multiagent chemotherapy. We aimed to evaluate the biological and clinical activity of neoadjuvant ribociclib plus letrozole in the luminal B subtype of early stage breast cancer. METHODS: CORALLEEN is a parallel-arm, multicentre, randomised, open-label, phase 2 trial completed across 21 hospitals in Spain. We recruited postmenopausal women (≥18 years) with stage I-IIIA hormone receptor-positive, Eastern Cooperative Oncology Group Performance Status 0-1, HER2-negative breast cancer and luminal B by PAM50 with histologically confirmed, operable primary tumour size of at least 2 cm in diameter as measured by MRI. Patients were randomly assigned (1:1) using a web-based system and permuted blocks of 25 to receive either six 28-days cycles of ribociclib (oral 600 mg once daily for 3 weeks on, 1 week off) plus daily letrozole (oral 2·5 mg/day) or four cycles of doxorubicin (intravenous 60 mg/m2) and cyclophosphamide (intravenous 600 mg/m2) every 21 days followed by weekly paclitaxel (intravenous 80 mg/m2) for 12 weeks. The total duration of the neoadjuvant therapy was 24 weeks. Randomisation was stratified by tumour size and nodal involvement. Samples were prospectively collected at baseline (day 0), day 15, and surgery. The primary endpoint was to evaluate the proportion of patients with PAM50 low-risk-of-relapse (ROR) disease at surgery in the modified intention-to-treat population including all randomly assigned patients who received study drug and had a baseline and at least one post-baseline measurement of ROR score. The PAM50 ROR risk class integrated gene expression data, tumour size, and nodal status to define prognosis. This trial was registered at ClinicalTrials.gov, NCT03248427. FINDINGS: Between July 27, 2017 to Dec 7, 2018, 106 patients were enrolled. At baseline, of the 106 patients, 92 (87%) patients had high ROR disease (44 [85%] of 52 in the ribociclib and letrozole group and 48 [89%] of 54 in the chemotherapy group) and 14 (13%) patients had intermediate-ROR disease (eight [15%] and six [11%]). Median follow-up was 200·0 days (IQR 191·2-206·0). At surgery, 23 (46·9%; 95% CI 32·5-61·7) of 49 patients in the ribociclib plus letrozole group and 24 (46·1%; 32·9-61·5) of 52 patients in the chemotherapy group were low-ROR. The most common grade 3-4 adverse events in the ribociclib plus letrozole group were neutropenia (22 [43%] of 51 patients) and elevated alanine aminotransferase concentrations (ten [20%]). The most common grade 3-4 adverse events in the chemotherapy group were neutropenia (31 [60%] of 52 patients) and febrile neutropenia (seven [13%]). No deaths were observed during the study in either group. INTERPRETATION: Our results suggest that some patients with high-risk, early stage, hormone receptor-positive, HER2-negative breast cancer could achieve molecular downstaging of their disease with CDK4/6 inhibitor and endocrine therapy. FUNDING: Novartis, Nanostring, Breast Cancer Research Foundation-AACR Career Development Award.

Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer.

BACKGROUND: Treatment options for triple-negative breast cancer remain limited. Activation of the PI3K pathway via loss of PTEN and/or INPP4B is common. Buparlisib is an orally bioavailable, pan-class I PI3K inhibitor. We evaluated the safety and efficacy of buparlisib in patients with metastatic triple-negative breast cancer. METHODS: This was a single-arm phase 2 study enrolling patients with triple-negative metastatic breast cancer. Patients were treated with buparlisib at a starting dose of 100 mg daily. The primary endpoint was clinical benefit, defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) for ≥ 4 months, per RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. A subset of patients underwent pre- and on-treatment tumor tissue biopsies for correlative studies. RESULTS: Fifty patients were enrolled. Median number of cycles was 2 (range 1-10). The clinical benefit rate was 12% (6 patients, all SD ≥ 4 months). Median PFS was 1.8 months (95% confidence interval [CI] 1.6-2.3). Median OS was 11.2 months (95% CI 6.2-25). The most frequent adverse events were fatigue (58% all grades, 8% grade 3), nausea (34% all grades, none grade 3), hyperglycemia (34% all grades, 4% grade 3), and anorexia (30% all grades, 2% grade 3). Eighteen percent of patients experienced depression (12% grade 1, 6% grade 2) and anxiety (10% grade 1, 8% grade 2). Alterations in PIK3CA/AKT1/PTEN were present in 6/27 patients with available targeted DNA sequencing (MSK-IMPACT), 3 of whom achieved SD as best overall response though none with clinical benefit ≥ 4 months. Of five patients with paired baseline and on-treatment biopsies, reverse phase protein arrays (RPPA) analysis demonstrated reduction of S6 phosphorylation in 2 of 3 patients who achieved SD, and in none of the patients with progressive disease. CONCLUSIONS: Buparlisib was associated with prolonged SD in a very small subset of patients with triple-negative breast cancer; however, no confirmed objective responses were observed. Downmodulation of key nodes in the PI3K pathway was observed in patients who achieved SD. PI3K pathway inhibition alone may be insufficient as a therapeutic strategy for triple-negative breast cancer. TRIAL REGISTRATION: NCT01790932 . Registered on 13 February 2013; NCT01629615 . Registered on 27 June 2012.

Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: In animal models of breast cancer, resistance to continuous use of letrozole can be reversed by withdrawal and reintroduction of letrozole. We therefore hypothesised that extended intermittent use of adjuvant letrozole would improve breast cancer outcome compared with continuous use of letrozole in postmenopausal women. METHODS: We did the multicentre, open-label, randomised, parallel, phase 3 SOLE trial in 240 centres (academic, primary, secondary, and tertiary care centres) in 22 countries. We enrolled postmenopausal women of any age with hormone receptor-positive, lymph node-positive, and operable breast cancer for which they had undergone local treatment (surgery with or without radiotherapy) and had completed 4-6 years of adjuvant endocrine therapy. They had to be clinically free of breast cancer at enrolment and without evidence of recurrent disease at any time before randomisation. We randomly assigned women (1:1) to treatment groups of either continuous use of letrozole (2·5 mg/day orally for 5 years) or intermittent use of letrozole (2·5 mg/day orally for 9 months followed by a 3-month break in years 1-4 and then 2·5 mg/day during all 12 months of year 5). Randomisation was done by principal investigators or designee at respective centres through the internet-based system of the International Breast Cancer Study Group, was stratified by type of previous endocrine therapy (aromatase inhibitors only vs selective oestrogen receptor modulators only vs both therapies), and used permuted block sizes of four and institutional balancing. No one was masked to treatment assignment. The primary endpoint was disease-free survival, analysed by the intention-to-treat principle using a stratified log-rank test. All patients in the intention-to-treat population who initiated protocol treatment during their period of trial participation were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00553410, and EudraCT, number 2007-001370-88; and long-term follow-up of patients is ongoing. FINDINGS: Between Dec 5, 2007, and Oct 8, 2012, 4884 women were enrolled and randomised after exclusion of patients at a non-adherent centre, found to have inadequate documentation of informed consent, immediately withdrew consent, or randomly assigned to intervention groups in error. 4851 women comprised the intention-to-treat population that compared extended intermittent letrozole use (n=2425) with continuous letrozole use (n=2426). After a median follow-up of 60 months (IQR 53-72), disease-free survival was 85·8% (95% CI 84·2-87·2) in the intermittent letrozole group compared with 87·5% (86·0-88·8) in the continuous letrozole group (hazard ratio 1·08, 95% CI 0·93-1·26; p=0·31). Adverse events were reported as expected and were similar between the two groups. The most common grade 3-5 adverse events were hypertension (584 [24%] of 2417 in the intermittent letrozole group vs 517 [21%] of 2411 in the continuous letrozole group) and arthralgia (136 [6%] vs 151 [6%]). 54 patients (24 [1%] in the intermittent letrozole group and 30 [1%] in the continuous letrozole group) had grade 3-5 CNS cerebrovascular ischaemia, 16 (nine [<1%] vs seven [<1%]) had grade 3-5 CNS haemorrhage, and 40 (19 [1%] vs 21 [1%]) had grade 3-5 cardiac ischaemia. In total, 23 (<1%) of 4851 patients died while on trial treatment (13 [<1%] of 2417 patients in the intermittent letrozole group vs ten [<1%] of 2411 in the continuous letrozole group). INTERPRETATION: In postmenopausal women with hormone receptor-positive breast cancer, extended use of intermittent letrozole did not improve disease-free survival compared with continuous use of letrozole. An alternative schedule of extended adjuvant endocrine therapy with letrozole, including intermittent administration, might be feasible and the results of the SOLE trial support the safety of temporary treatment breaks in selected patients who might require them. FUNDING: Novartis and the International Breast Cancer Study Group.

Physical activity and breast cancer risk by pathological subtype.

OBJECTIVE: To examine the influence of physical activity on breast cancer risk and evaluate whether adherence to international recommendations is associated with a decreased risk. METHODS: This is a multicenter matched case-control study where 698 pairs completed a physical activity questionnaire. Recreational physical activity during the last year was quantified in metabolic equivalent hours per week (MET-h/week) and categorized in activities of moderate (3.0-5.9 MET) and vigorous (>6 MET) intensity. The adherence to World Cancer Research Fund and the American Institute for Cancer Research recommendation was also assessed. The association with breast cancer risk, overall and by pathologic subtype, was evaluated using conditional and multinomial logistic regression models. RESULTS: Mean MET-h/week was 16.6 among cases and 20.4 among controls. Premenopausal breast cancer risk decreased by 5% (P=0.007) for every 6 MET-h/week increase in energy expenditure. By contrast, postmenopausal women needed to do more intense exercise to observe benefits. The protection was more pronounced for nulliparous women, as well as for hormone receptor positive and HER2+ tumors. Physically inactive women displayed a 71% increased risk when compared with those who met the international recommendation (P=0.001). Finally, women who were inactive during the previous year, regardless of the overall physical activity reported in previous periods, showed an increased risk when compared to always active women. CONCLUSIONS: Women who report adherence to international physical activity recommendations entail a significant decrease in risk for all pathologic breast cancer subtypes. This is of particular interest in Spain, where a significant increase in overweight and obesity in recent decades is observed.

SOLTI NeoPARP: a phase II randomized study of two schedules of iniparib plus paclitaxel versus paclitaxel alone as neoadjuvant therapy in patients with triple-negative breast cancer.

Iniparib is an investigational agent with antitumor activity of controversial mechanism of action. Two previous trials in advanced triple-negative breast cancer (TNBC) in combination with gemcitabine and carboplatin showed some evidence of efficacy that was not confirmed. This phase II randomized neoadjuvant study was designed to explore its activity and tolerability with weekly paclitaxel (PTX) as neoadjuvant treatment in TNBC patients. 141 patients with Stage II-IIIA TNBC were randomly assigned to receive PTX (80 mg/m(2), d1; n = 47) alone or in combination with iniparib, either once-weekly (PWI) (11.2 mg/kg, d1; n = 46) or twice-weekly (PTI) (5.6 mg/kg, d1, 4; n = 48) for 12 weeks. Primary endpoint was pathologic complete response (pCR) in the breast. pCR rate was similar among the three arms (21, 22, and 19 % for PTX, PWI, and PTI, respectively). Secondary efficacy endpoints were comparable: pCR in breast and axilla (21, 17, and 19 %); best overall response in the breast (60, 61, and 63 %); and breast conservation rate (53, 54, and 50 %). Slightly more patients in the PTI arm presented grade 3/4 neutropenia (4, 0, and 10 %). Grade 1/2 (28, 22, and 29 %), but no grade 3/4 neuropathy, was observed. There were no differences in serious adverse events and treatment-emergent adverse events leading to treatment discontinuation among the three arms. Addition of iniparib to weekly PTX did not add relevant antitumor activity or toxicity. These results do not support further evaluation of the combination of iniparib at these doses plus paclitaxel in early TNBC.

Efficacy and safety of neoadjuvant chemotherapy with concurrent liposomal-encapsulated doxorubicin, paclitaxel and trastuzumab for human epidermal growth factor receptor 2-positive breast cancer in clinical practice.

BACKGROUND: Based on previous results obtained with non-pegylated liposomal-encapsulated doxorubicin (TLC-D99) together with paclitaxel and trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer (BC), a similar regimen was evaluated in the neoadjuvant setting in a prospectively selected series of consecutive patients with clinical stage II-III BC. Primary and secondary objectives included the rate of pathologic complete response (pCR), safety, and predictive factors of pCR. METHODS: Patients received six cycles of TLC-D99 (50 mg/m(2) every 3 weeks), paclitaxel (80 mg/m(2) weekly) and trastuzumab (4 mg/kg initial dose and 2 mg/kg weekly). All patients underwent surgery after treatment. pCR was defined as the absence of invasive cancer cells in the breast and the axilla. RESULTS: Sixty-two patients with a median age of 46.6 years were analyzed. Stage IIIA was diagnosed in 43.5% of patients and 14.5% had inflammatory BC. Conservative surgery was performed in 46.8% of the patients and pCR was achieved in 63% (95% CI 50.5-75.5). Patients with estrogen receptor (ER)-negative tumors presented a significantly higher pCR rate than patients with ER-positive tumors (74.4 vs 43.5%; P = 0.028). Forty-five patients (72.6%) completed study treatment and 80.6% received at least five treatment cycles. No patients developed congestive heart failure and 14.5% of patients showed a ≥ 10 % decrease in the left ventricular ejection fraction. CONCLUSION: The triple combination therapy assessed is effective and safe, offering a high pCR rate in patients with HER2-positive BC.

Safety profile of trastuzumab deruxtecan in advanced breast cancer: Expert opinion on adverse event management.

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that targets human epidermal growth factor receptor 2 (HER2) and has shown promising results in the treatment of advanced/metastatic breast cancer. The objective of this report is to provide guidance on the prophylaxis, monitoring, and management of adverse events (AEs) in patients with breast cancer treated with T-DXd, and to emphasize that proper management of AEs is needed to optimize the effectiveness of T-DXd treatment and reduce the number of discontinuations. The article covers various aspects of T-DXd treatment, including its clinical efficacy, safety profile, and dosing considerations, and provides practical recommendations for managing AEs, such as nausea/vomiting, interstitial lung disease, and hematologic toxicity. Although there are still many knowledge gaps about the cause and incidence of AEs in real-world patients, this document may serve as a valuable resource for clinicians who are involved in the care of breast cancer patients receiving T-DXd treatment.

Computational model predicts patient outcomes in Luminal B breast cancer treated with endocrine therapy and CDK4/6 inhibition.

PURPOSE: Development of a computational biomarker to predict, prior to treatment, the response to CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy in patients with breast cancer. EXPERIMENTAL DESIGN: A mechanistic mathematical model that accounts for protein signaling and drug mechanisms of action was developed and trained on extensive, publicly available data from breast cancer cell lines. The model was built to provide a patient-specific response score based on the expression of six genes (CCND1, CCNE1, ESR1, RB1, MYC and CDKN1A). The model was validated in five independent cohorts of 148 patients in total with early-stage or advanced breast cancer treated with endocrine therapy and CDK4/6i. Response was measured either by evaluating Ki67 levels and PAM50 risk of relapse (ROR) after neoadjuvant treatment or by evaluating progression-free survival (PFS). RESULTS: The model showed significant association with patient´s outcomes in all five cohorts. The model predicted high Ki67 (area under the curve; AUC (95% confidence interval) of 0.80 (0.64 - 0.92), 0.81 (0.60 - 1.00) and 0.80 (0.65 - 0.93)) and high PAM50 ROR (AUC of 0.78 (0.64 - 0.89)). This observation was not obtained in patients treated with chemotherapy. In the other cohorts, patient stratification based on the model prediction was significantly associated with PFS (hazard ratio=2.92 (95% CI 1.08 - 7.86), p=0.034 and HR=2.16 (1.02 4.55), p=0.043). CONCLUSION: A mathematical modeling approach accurately predicts patient outcome following CDK4/6i plus endocrine therapy, which marks a step towards more personalized treatments in patients with Luminal B breast cancer.

Cell-cycle inhibition and immune microenvironment in breast cancer treated with ribociclib and letrozole or chemotherapy.

In this study, we performed genomic analyses of cell cycle and tumor microenvironment changes during and after ribociclib and letrozole or chemotherapy in the CORALLEEN trial. 106 women with untreated PAM50-defined Luminal B early breast cancers were randomly assigned to receive neoadjuvant ribociclib and letrozole or standard-of-care chemotherapy. Ki67 immunohistochemistry, tumor-infiltrating lymphocytes quantification, and RNA sequencing were obtained from tissue biopsies pre-treatment, on day 14 of treatment, and tumor specimens from surgical resection. Results showed that at surgery, Ki67 and the PAM50 proliferation scores were lower after ribociclib compared to chemotherapy. However, consistent reactivation of tumor cell proliferation from day 14 to surgery was only observed in the ribociclib arm. In tumors with complete cell cycle arrest (CCCA) at surgery, PAM50 proliferation scores were lower in the ribociclib arm compared to chemotherapy (p < 0.001), whereas the opposite was observed with tumor cellularity (p = 0.002). Gene expression signatures (GES) associated with antigen-presenting cells (APCs) and innate immune system activity showed increased expression post-chemotherapy but decreased expression post-ribociclib. Interferon-associated GES had decreased expression with CCCA and increased expression with non-CCCA. Our findings suggest that while both treatment strategies decreased proliferation, the depth and the patterns over time differed by treatment arm. Immunologically, ribociclib was associated with downregulated GES associated with APCs and the innate immune system in Luminal B tumors, contrary to existing preclinical data. Further studies are needed to understand the effect of CDK4/6 inhibition on the tumor cells and microenvironment, an effect which may vary according to tumor subtypes.

Impact of coadministration of proton-pump inhibitors and palbociclib in hormone receptor-positive/HER2-negative advanced breast cancer.

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.

Obesity and survival in operable breast cancer patients treated with adjuvant anthracyclines and taxanes according to pathological subtypes: a pooled analysis.

INTRODUCTION: Obesity is an unfavorable prognostic factor in breast cancer (BC) patients regardless of menopausal status and treatment received. However, the association between obesity and survival outcome by pathological subtype requires further clarification. METHODS: We performed a retrospective analysis including 5,683 operable BC patients enrolled in four randomized clinical trials (GEICAM/9906, GEICAM/9805, GEICAM/2003-02, and BCIRG 001) evaluating anthracyclines and taxanes as adjuvant treatments. Our primary aim was to assess the prognostic effect of body mass index (BMI) on disease recurrence, breast cancer mortality (BCM), and overall mortality (OM). A secondary aim was to detect differences of such prognostic effects by subtype. RESULTS: Multivariate survival analyses adjusting for age, tumor size, nodal status, menopausal status, surgery type, histological grade, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, chemotherapy regimen, and under-treatment showed that obese patients (BMI 30.0 to 34.9) had similar prognoses to that of patients with a BMI < 25 (reference group) in terms of recurrence (Hazard Ratio [HR] = 1.08, 95% Confidence Interval [CI] = 0.90 to 1.30), BCM (HR = 1.02, 0.81 to 1.29), and OM (HR = 0.97, 0.78 to 1.19). Patients with severe obesity (BMI ≥ 35) had a significantly increased risk of recurrence (HR = 1.26, 1.00 to 1.59, P = 0.048), BCM (HR = 1.32, 1.00 to 1.74, P = 0.050), and OM (HR = 1.35, 1.06 to 1.71, P = 0.016) compared to our reference group. The prognostic effect of severe obesity did not vary by subtype. CONCLUSIONS: Severely obese patients treated with anthracyclines and taxanes present a worse prognosis regarding recurrence, BCM, and OM than patients with BMI < 25. The magnitude of the harmful effect of BMI on survival-related outcomes was similar across subtypes.

Observational study of HR+/HER2- metastatic breast cancer patients treated with abemaciclib in Spain in the Named Patient Use Program (AbemusS).

INTRODUCTION/OBJECTIVES: To describe abemaciclib use in patients with hormone receptor-positive, human epidermal growth factor receptor-negative (HR+/HER2-) metastatic breast cancer (mBC) who participated in the Named Patient Use program (NPU) in Spain. MATERIAL AND METHODS: This retrospective study was based on medical record review of patients across 20 centers during 2018/2019. Patients were followed up until death, enrolment in a clinical trial, loss of follow-up or study end. Clinical and demographic characteristics, treatment patterns and abemaciclib effectiveness were analyzed; time-to-event and median times were estimated using the Kaplan-Meier (KM) method. RESULTS: The study included 69 female patients with mBC (mean age 60.4 ± 12.4 years), 86% of whom had an initial diagnosis of early BC and 20% had an ECOG ≥ 2. Median follow-up was 23 months (range 16-28). Metastases were frequently observed in bone (79%) and visceral tissue (65%), with 47% having metastases in > 2 sites. Median number of treatment lines before abemaciclib was 6 (range 1-10). Abemaciclib monotherapy was received by 72% of patients and combination therapy with endocrine therapy by 28% of patients; 54% of patients required dose adjustments, with a median time to first adjustment of 1.8 months. Abemaciclib was discontinued in 86% of patients after a median of 7.7 months (13.2 months for combination therapy and 7.0 months for monotherapy) mainly due to disease progression (69%). CONCLUSION: These results suggest that abemaciclib is effective, as monotherapy and in combination, for patients with heavily pretreated mBC, consistent with clinical trial results.

HOPE (SOLTI-1903) breast cancer study: real-world, patient-centric, clinical practice study to assess the impact of genomic data on next treatment decision-choice in patients with locally advanced or metastatic breast cancer.

Background: Metastatic breast cancer (mBC) causes nearly all BC-related deaths. Next-generation sequencing (NGS) technologies allow for the application of personalized medicine using targeted therapies that could improve patients' outcomes. However, NGS is not routinely used in the clinical practice and its cost induces access-inequity among patients. We hypothesized that promoting active patient participation in the management of their disease offering access to NGS testing and to the subsequent medical interpretation and recommendations provided by a multidisciplinary molecular advisory board (MAB) could contribute to progressively overcome this challenge. We designed HOPE (SOLTI-1903) breast cancer trial, a study where patients voluntarily lead their inclusion through a digital tool (DT). The main objectives of HOPE study are to empower mBC patients, gather real-world data on the use of molecular information in the management of mBC and to generate evidence to assess the clinical utility for healthcare systems. Trial design: After self-registration through the DT, the study team validates eligibility criteria and assists patients with mBC in the subsequent steps. Patients get access to the information sheet and sign the informed consent form through an advanced digital signature. Afterwards, they provide the most recent (preferably) metastatic archival tumor sample for DNA-sequencing and a blood sample obtained at the time of disease progression for ctDNA analysis. Paired results are reviewed by the MAB, considering patient's medical history. The MAB provides a further interpretation of molecular results and potential treatment recommendations, including ongoing clinical trials and further (germline) genetic testing. Participants self-document their treatment and disease evolution for the next 2 years. Patients are encouraged to involve their physicians in the study. HOPE also includes a patient empowerment program with educational workshops and videos about mBC and precision medicine in oncology. The primary endpoint of the study was to describe the feasibility of a patient-centric precision oncology program in mBC patients when a comprehensive genomic profile is available to decide on a subsequent line of treatment. Clinical trial registration: www.soltihope.com, identifier NCT04497285.

Oncolytic viruses: A new immunotherapeutic approach for breast cancer treatment?

Immunotherapy has revolutionized the oncology field during the last years, mainly with the introduction of immune checkpoint inhibitors in the clinical routine. Despite the recent approval of these drugs for the treatment of triple-negative breast cancer, most breast cancer patients cannot benefit from immunotherapy as most tumors are not considered immunoreactive. Therefore, new strategies must be developed to bring immunotherapy closer to breast cancer patients. The introduction of oncolytic viruses in the immuno-oncology field has shown promising results in cancer treatment, including breast cancer. However, a better understanding of their mechanisms of action, increase evidence of safety and efficacy, and the implications of its use as a systemic therapy must be examined in more depth. This review provides a summary of oncolytic virotherapy in the context of breast cancer, both in the pre-clinical and clinical setting.

Pre-operative ribociclib plus letrozole versus chemotherapy: Health-related quality of life outcomes from the SOLTI CORALLEEN trial.

INTRODUCTION: In the phase II CORALLEEN trial, patients with PAM50 luminal B early breast cancer (EBC) were randomised to neoadjuvant ribociclib plus letrozole (R + L) or chemotherapy based on anthracyclines and taxanes. Results from the primary efficacy analysis showed a similar proportion of patients with response at surgery in both groups. How health-related quality of life (HRQoL) outcomes with R + L compare with chemotherapy in EBC setting is still unknown. Here, we report the results of the HRQoL analysis from the CORALLEEN study. METHODS: A total of 106 women were randomised 1:1 to receive neoadjuvant R + L (n = 52) or chemotherapy (n = 54). Patient-reported outcomes were assessed using two questionnaires: EORTC QLQ-C30 and EORTC QLQ-BR23. Change from baseline in the global health status, functional, and symptom scales was analysed using linear mixed-effect models, and between-treatment differences were estimated along with 95% confidence interval (95% CI). RESULTS: At baseline, the overall questionnaire available rate was 94.3%, and patient-reported outcomes were similar between treatment groups. At the end of the study treatment (24 weeks), patients receiving R + L showed better global health status scores with a between-treatment difference of 17.7 points (95% CI 9.2-26.2; p-value <0.001). The R + L group also presented numerically better outcomes in all functional and symptom scales. The larger between-treatment differences in symptom severity were found in fatigue (-28.9; 95% CI -38.5 to -19.3), appetite loss (-23; 95% CI -34.9 to -11.2) and systematic therapy side-effects (-11.4; 95% CI -18.3 to -4.6). CONCLUSIONS: Neoadjuvant R + L was associated with better HRQoL outcomes compared with chemotherapy in patients with luminal B EBC. REGISTRATION IDENTIFICATION: ClinicalTrials.gov Identifier: NCT03248427.

The role of CDK4/6 inhibitors in early breast cancer.

The use of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) has proven to be a successful strategy in the treatment of advanced hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC), leading to a strong interest in their possible role in the treatment of early luminal BC. In this review we collect the most relevant and recent information on the use of CDK4/6i for the treatment of early BC in the neoadjuvant and adjuvant settings. Specifically, we evaluate the results of the large phase 3 adjuvant trials recently released, which have yielded apparently divergent results. We also examine the relevance of biomarkers as response predictive factors for CDI4/6i, the combination between radiotherapy and CDK4/6i, and provide a critical discussion on the evidence that we have so far and future directions of the role of these drugs in the treatment of early BC.