First-line therapy with palbociclib in patients with advanced HR+/HER2- breast cancer: The real-life study PALBOSPAIN.

PURPOSE: To evaluate the efficacy and safety of first-line therapy with palbociclib in a Spanish cohort treated after palbociclib approval. METHODS: PALBOSPAIN is an observational, retrospective, multicenter study evaluating real-world patterns and outcomes with 1 L palbociclib in men and women (any menopausal status) with advanced HR+/HER2- BC diagnosed between November 2017 and November 2019. The primary endpoint was real-world progression-free survival (rw-PFS). Secondary endpoints included overall survival (OS), the real-world response rate (rw-RR), the clinical benefit rate, palbociclib dose reduction, and safety. RESULTS: A total of 762 patients were included. The median rw-PFS and OS were 24 months (95% CI 21-27) and 42 months (40-not estimable [NE]) in the whole population, respectively. By cohort, the median rw-PFS and OS were as follows: 28 (95% CI 23-39) and 44 (95% CI 38-NE) months in patients with de novo metastatic disease, 13 (95% CI 11-17) and 36 months (95% CI 31-41) in patients who experienced relapse < 12 months after the end of ET, and 31 months (95% CI 26-37) and not reached (NR) in patients who experienced relapse > 12 months after the end of ET. rw-PFS and OS were longer in patients with oligometastasis and only one metastatic site and those with non-visceral disease. The most frequent hematologic toxicity was neutropenia (72%; grade ≥ 3: 52.5%), and the most common non-hematologic adverse event was asthenia (38%). CONCLUSION: These findings, consistent with those from clinical trials, support use of palbociclib plus ET as 1 L for advanced BC in the real-world setting, including pre-menopausal women and men. TRIAL REGISTRATION NUMBER: NCT04874025 (PALBOSPAIN). Date of registration: 04/30/2021 retrospectively registered.

Phosphoproteomic analysis of neoadjuvant breast cancer suggests that increased sensitivity to paclitaxel is driven by CDK4 and filamin A.

Precision oncology research is challenging outside the contexts of oncogenic addiction and/or targeted therapies. We previously showed that phosphoproteomics is a powerful approach to reveal patient subsets of interest characterized by the activity of a few kinases where the underlying genomics is complex. Here, we conduct a phosphoproteomic screening of samples from HER2-negative female breast cancer receiving neoadjuvant paclitaxel (N = 130), aiming to find candidate biomarkers of paclitaxel sensitivity. Filtering 11 candidate biomarkers through 2 independent patient sets (N = 218) allowed the identification of a subgroup of patients characterized by high levels of CDK4 and filamin-A who had a 90% chance of achieving a pCR in response to paclitaxel. Mechanistically, CDK4 regulates filamin-A transcription, which in turn forms a complex with tubulin and CLIP-170, which elicits increased binding of paclitaxel to microtubules, microtubule acetylation and stabilization, and mitotic catastrophe. Thus, phosphoproteomics allows the identification of explainable factors for predicting response to paclitaxel.

Randomized phase II study of fulvestrant plus palbociclib or placebo in endocrine-sensitive, hormone receptor-positive/HER2-advanced breast cancer: GEICAM/2014-12 (FLIPPER).

BACKGROUND: The potential benefit of adding palbociclib to fulvestrant as first-line treatment in hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative endocrine-sensitive advanced breast cancer (ABC) patients remains uncharacterized. PATIENTS AND METHODS: In this randomized (1:1), double-blind, phase II study, postmenopausal women with HR-positive, HER2-negative ABC with de novo metastatic disease or those who relapsed after >12 months of adjuvant endocrine therapy received palbociclib/fulvestrant or placebo/fulvestrant. Stratification was based on recurrent versus de novo metastatic disease and visceral involvement. The primary objective was one-year progression-free survival (PFS-1y) rate. The sample size was 190 patients. The two-sided alpha of 0.2, 80% of power to detect a difference between the arms, assuming PFS rates of 0.695 and 0.545 for palbociclib/fulvestrant and placebo/fulvestrant, respectively. RESULTS: In total, 189 patients were randomized to palbociclib/fulvestrant ([n = 94] or placebo/fulvestrant [n = 95]). 45.5% and 60.3% of patients had de novo metastatic disease and visceral involvement, respectively. PFS-1y rates were 83.5% and 71.9% in the palbociclib/fulvestrant and placebo/fulvestrant arms, (HR 0.55, 80% CI 0.36-0.83, P = 0.064). The median PFS were 31.8 and 22.0 months for the palbociclib/fulvestrant and placebo/fulvestrant arms (aHR 0.48, 80% CI 0.37-0.64, P = 0.001). The most frequent grade 3-4 adverse events were neutropenia (68.1% vs. 0%), leucopenia (26.6% vs. 0%), anemia (3.2% vs. 0%), and lymphopenia (14.9% vs. 2.1%) for the palbociclib/fulvestrant and placebo/fulvestrant, respectively. The most frequent non-hematologic grade 3-4 adverse event was fatigue (4.3% vs. 0%). CONCLUSIONS: Palbociclib/fulvestrant demonstrated better PFS-1y rates and median PFS than placebo/fulvestrant in HR-positive/HER2-negative endocrine-sensitive ABC patients.

Prospective, multicenter study on the economic and clinical impact of gene-expression assays in early-stage breast cancer from a single region: the PREGECAM registry experience.

INTRODUCTION: The aim of this study is to evaluate the cost-effectiveness and impact of gene-expression assays (GEAs) on treatment decisions in a real-world setting of early-stage breast cancer (ESBC) patients. METHODS: This is a regional, prospective study promoted by the Council Health Authorities in Madrid. Enrolment was offered to women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative, node-negative or micrometastatic, stage I or II breast cancer from 21 hospitals in Madrid. Treatment recommendations were recorded before and after knowledge of tests results. An economic model compared the cost-effectiveness of treatment, guided by GEAs or by common prognostic factors. RESULTS: 907 tests (440 Oncotype DX® and 467 MammaPrint®) were performed between February 2012 and November 2014. Treatment recommendation changed in 42.6% of patients. The shift was predominantly from chemohormonal (CHT) to hormonal therapy (HT) alone, in 30.5% of patients. GEAs increased patients' confidence in treatment decision making. Tumor grade, progesterone receptor positivity and Ki67 expression were associated with the likelihood of change from CHT to HT (P < 0.001) and from HT to CHT (P < 0.001). Compared with current clinical practice genomic testing increased quality-adjusted life years by 0.00787 per patient and was cost-saving from a national health care system (by 13.867€ per patient) and from a societal perspective (by 32.678€ per patient). CONCLUSION: Using GEAs to guide adjuvant therapy in ESBC is cost-effective in Spain and has a significant impact on treatment decisions.

Evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for hormone receptor-positive metastatic breast cancer: a pooled analysis from the LEA (GEICAM/2006-11_GBG51) and CALGB 40503 (Alliance) trials.

BACKGROUND: Randomised trials comparing the efficacy of standard endocrine therapy (ET) versus experimental ET + bevacizumab (Bev) in 1st line hormone receptor-positive patients with metastatic breast cancer have thus far shown conflicting results. PATIENTS AND METHODS: We pooled data from two similar phase III randomised trials of ET ± Bev (LEA and Cancer and Leukemia Group B 40503) to increase precision in estimating treatment effect. Primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR) and safety. Exploratory analyses were performed within subgroups defined by patients with recurrent disease, de novo disease, prior endocrine sensitivity or resistance and reported grades III-IV hypertension and proteinuria. RESULTS: The pooled sample consisted of 749 patients randomised to ET or ET + Bev. Median PFS was 14.3 months for ET versus 19 months for ET + Bev (unadjusted hazard ratio [HR] 0.77; 95% confidence interval [CI] 0.66-0.91; p < 0.01). ORR and CBR with ET and ET + Bev were 40 versus 61% (p < 0.01) and 64 versus 77% (p < 0.01), respectively. There was no difference in OS (HR 0.96; 95% CI 0.77-1.18; p = 0.68). PFS was superior for ET + Bev for endocrine-sensitive patients (HR 0.68; 95% CI 0.53-0.89; p = 0.004). Grade III-IV hypertension (2.2 versus 20.1%), proteinuria (0 versus 9.3%), cardiovascular (0.5 versus 4.2%) and liver events (0 versus 2.9%) were significantly higher for ET + Bev (all p < 0.01). Hypertension and proteinuria were not predictors of efficacy (interaction test p = 0.33). CONCLUSION: The addition of Bev to ET increased PFS overall and in endocrine-sensitive patients but not OS at the expense of significant additional toxicity. TRIALS REGISTRATION: ClinicalTrial.Gov NCT00545077 and NCT00601900.

Safety of everolimus plus exemestane in patients with hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer: results of phase IIIb BALLET trial in Spain

Background: Everolimus with exemestane has shown promising activity in patients with hormone-receptor (HR)-positive HER2-negative endocrine-resistant advanced breast cancer. It is necessary, therefore, to characterize the safety profile of this new combination in the real-world clinical setting and in the broadest possible population. Patients and methods: Post-menopausal women with HR-positive HER2-negative advanced breast cancer progressing after prior non-steroidal aromatase inhibitors (NSAIs) were included. The objectives of this analysis were to evaluate the safety profile of this combination in a subset of Spanish patients in the BALLET trial and to characterize grade 3 and 4 adverse events (AEs) in routine clinical practice in Spain. Results: Between September 2012 and July 2013, 429 patients (20% of the overall study population) were included in the BALLET study in 52 hospitals in Spain, of whom 100 (23%) were ≥ 70 years. The median treatment duration was 3.14 and 3.03 months for exemestane and everolimus, respectively. The most common reasons for discontinuation of treatment were local reimbursement of everolimus (43%), followed by disease progression (31%) and the incidence of AEs (15%). The most frequent AEs causing permanent discontinuation were pneumonitis (4%), asthenia (2%) and stomatitis (2%). Overall, 87% of patients experienced at least one AE of any grade, 30% of patients at least one grade 3 AE and 2% of patients a grade 4 AE. Conclusion: The safety profile in Spanish patients of the BALLET trial is consistent with the results obtained in the overall population of the trial, as well as in previous clinical trials

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Open-label randomised phase III trial of vinflunine versus an alkylating agent in patients with heavily pretreated metastatic breast cancer.

Background: There is no standard treatment after progression on second-line chemotherapy for metastatic breast cancer (MBC). We compared vinflunine with physician's choice of alkylating agent (AA) for patients with heavily pretreated MBC. Patients and methods: In this open-label phase III trial, patients with MBC were included if they had received at least two prior chemotherapy regimens for MBC and had received anthracycline, taxane, antimetabolite and vinca alkaloid therapy. Patients were no longer candidates for these chemotherapies because of resistance and/or intolerance. Patients were randomised to either vinflunine 280 mg/m2 intravenously every 3 weeks (q3w) or AA monotherapy q3w. Stratification factors were performance status, number of prior chemotherapy lines for MBC, disease measurability and study site. The primary end point was overall survival (OS). Results: A total of 594 patients were randomised (298 to vinflunine, 296 to AA). There was no difference between treatment arms in OS (hazard ratio 1.04, P = 0.67; median 9.1 months for vinflunine versus 9.3 months for AA), progression-free survival (hazard ratio 0.94, P = 0.49; median 2.5 versus 1.9 months, respectively) or overall response rate (6% versus 4%, respectively). However, the disease control rate was significantly higher with vinflunine than AA (44% versus 35%, respectively; P = 0.04). The most common adverse events (any grade) were haematological and gastrointestinal disorders and asthenia in both arms. The most common grade 3/4 adverse events were neutropenia (19% versus 11% with vinflunine versus AA, respectively) and asthenia (10% versus 4%). Conclusions: Vinflunine 280 mg/m2 q3w did not improve OS compared with the physician's choice of AA as third- or later-line therapy for MBC. Vinflunine demonstrated an acceptable safety profile, suggesting that vinflunine 320 mg/m2 merits evaluation. ClinicalTrials.gov: NCT01091168.

Safety of everolimus plus exemestane in patients with hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer: results of phase IIIb BALLET trial in Spain.

BACKGROUND: Everolimus with exemestane has shown promising activity in patients with hormone-receptor (HR)-positive HER2-negative endocrine-resistant advanced breast cancer. It is necessary, therefore, to characterize the safety profile of this new combination in the real-world clinical setting and in the broadest possible population. PATIENTS AND METHODS: Post-menopausal women with HR-positive HER2-negative advanced breast cancer progressing after prior non-steroidal aromatase inhibitors (NSAIs) were included. The objectives of this analysis were to evaluate the safety profile of this combination in a subset of Spanish patients in the BALLET trial and to characterize grade 3 and 4 adverse events (AEs) in routine clinical practice in Spain. RESULTS: Between September 2012 and July 2013, 429 patients (20% of the overall study population) were included in the BALLET study in 52 hospitals in Spain, of whom 100 (23%) were ≥ 70 years. The median treatment duration was 3.14 and 3.03 months for exemestane and everolimus, respectively. The most common reasons for discontinuation of treatment were local reimbursement of everolimus (43%), followed by disease progression (31%) and the incidence of AEs (15%). The most frequent AEs causing permanent discontinuation were pneumonitis (4%), asthenia (2%) and stomatitis (2%). Overall, 87% of patients experienced at least one AE of any grade, 30% of patients at least one grade 3 AE and 2% of patients a grade 4 AE. CONCLUSION: The safety profile in Spanish patients of the BALLET trial is consistent with the results obtained in the overall population of the trial, as well as in previous clinical trials.

Pegylated liposomal doxorubicin plus cyclophosphamide followed by paclitaxel as primary chemotherapy in elderly or cardiotoxicity-prone patients with high-risk breast cancer: results of the phase II CAPRICE study.

Anthracycline and taxane-based primary chemotherapy (PCT) is the standard treatment for high-risk breast cancer (HRBC). However, conventional anthracyclines are not commonly used in elderly patients or those prone to cardiotoxicity. Pegylated liposomal doxorubicin, (PLD) has comparable efficacy, but less cardiotoxicity than conventional anthracyclines. We conducted a phase II single-arm trial to assess the efficacy and safety of PCT based on PLD followed by paclitaxel (PTX) in a HRBC population usually undertreated. Fifty patients with stage II-IIIB breast cancer and at least one risk factor for developing cardiotoxicity initiated PLD 35 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 4 weeks for four cycles, followed by 80 mg/m(2) weekly PTX for 12. Close cardiac monitoring was performed. Primary endpoint was the pathological complete response rate (pCR) in the breast. Treatment delivery and toxicities were assessed. Eighty-four per cent of patients were older than 65 years, 64 % suffered from hypertension, and 10 % had prior cardiac disease. In an intention-to-treat analysis, breast pCR was 32 % (95 % CI 19.5-46.7 %) and pCR in breast and axilla was 24 % (95 % CI 12.1-35.8 %). At diagnosis only, 26 % of patients were candidates for breast conservative surgery, which increased to 58.7 % after PCT. No significant decrease in left ventricular ejection fraction was seen. PLD followed by PTX was feasible in a fragile population of patients who were not candidates for conventional doxorubicin. Moreover, it achieved a pCR similar to standard therapy and could therefore be an option for elderly patients or cardiotoxicity-prone who present HRBC.

Use of bevacizumab as a first-line treatment for metastatic breast cancer.

OBJECTIVE: During clinical practice, it can be challenging, given the lack of response biomarkers, to identify the patients with metastatic breast cancer (mbca) who would benefit most from the addition of bevacizumab to first-line standard chemotherapy. The aim of the present review was to summarize the relevant scientific evidence and to discuss the experience of a group of experts in using bevacizumab to treat mbca. METHODS: A panel of 17 Spanish oncology experts met to discuss the literature and their experience in the use of bevacizumab as first-line treatment for mbca. During the meeting, discussions focused on three main issues: the profile of the patients who could benefit most from bevacizumab, the optimal bevacizumab treatment duration, and the safety profile of bevacizumab. RESULTS: The subset of mbca patients who would benefit the most from the addition of bevacizumab to first-line standard chemotherapy are those with clinically defined aggressive disease. Treatment with bevacizumab should be maintained until disease progression or the appearance of unacceptable toxicity. In the mbca setting, the toxicity profile of bevacizumab is well known and can be managed in clinical practice after adequate training. CONCLUSIONS: This expert group recommends administering bevacizumab as first-line treatment in patients with clinically aggressive disease.