Palbociclib is a CDK4/6 inhibitor with demonstrated efficacy and safety in combination with endocrine therapy in advanced luminal breast cancer (LBC). We evaluated the respective efficacy and safety ...of chemotherapy and letrozole–palbociclib (LETPAL) combination as neoadjuvant treatment in patients with high-risk LBC.
NeoPAL (UCBG10/4, NCT02400567) is a randomised, parallel, non-comparative phase II study. Patients with ER-positive, HER2-negative, Prosigna®-defined luminal B, or luminal A and node-positive, stage II–III breast cancer, not candidate for breast-conserving surgery, were randomly assigned to either letrozole (2.5 mg daily) and palbociclib (125 mg daily, 3 weeks/4) during 19 weeks, or to FEC100 (5FU 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2)×3 21-day courses followed by docetaxel 100 mg/m2×3 21-day courses. Primary end point was residual cancer burden (RCB 0–I rate). Secondary end points included clinical response, proliferation-based markers, and safety.
Overall, 106 patients were randomised median Prosigna® ROR Score 71 (22–93). RCB 0–I was observed in four and eight patients in LETPAL 7.7% (95% CI 0.4–14.9) and chemotherapy 15.7% (95% CI 5.7–25.7) arms, respectively. Pathological complete response rates were 3.8% and 5.9%. Clinical response (75%) and breast-conserving surgery rates (69%) were similar in both arms. Preoperative Endocrine Prognostic Index 0 scores (breast cancer-specific survival) were observed in 17.6% and 8.0% of patients in LETPAL and chemotherapy arms, respectively. Safety profile was as expected, with 2 versus 17 serious adverse events (including 11 grade 4 serious AEs in the chemotherapy arm).
LETPAL combination was associated with poor pathological response but encouraging clinical and biomarker responses in Prosigna®-defined high-risk LBC. Contemporary chemotherapy regimen was associated with poor pathological and biomarker responses, with a much less favourable safety profile. LETPAL combination might represent an alternative to chemotherapy in early high-risk LBC.
NCT02400567.
Signaling involved in osteoblastic cell differentiation remains largely unknown. This study further investigates mechanisms involved in BMP‐2‐induced osteoblastic cell differentiation. We report that ...BMP‐2 can activate JNK and p38 in osteoblastic cells and provide evidences that these MAP kinases have distinct roles in regulating alkaline phosphatase and osteocalcin expression.
Introduction: Bone morphogenetic protein (BMP)‐2 exerts many of its biological effects through activation of the Smad pathway. Cooperative interactions between the Smads and the stress‐activated protein kinase (SAPK) p38 and c‐Jun‐NH2‐terminal kinase (JNK) pathways have recently been observed in TGF‐β signaling.
Materials and Methods: Activation of mitogen‐activated protein (MAP) kinases by BMP‐2 and the role of these signaling pathways for cell differentiation induced by BMP‐2 was investigated in mouse MC3T3‐E1 and primary cultured calvaria‐derived osteoblastic cells using immunoprecipitation, in vitro kinase assay and Western blot analysis, as well as specific MAP kinase inhibitors.
Results: Associated with the rapid activation of Smads, BMP‐2 barely affected extracellular‐signal regulated kinase (ERK) activity, whereas it induced a transient activation of p38 and JNK. The role of p38 and JNK in mediating BMP‐2‐induced stimulation of osteoblastic cell differentiation was evaluated using the respective specific inhibitors SB203580 and SP600125. Inhibition of p38 by SB203580 was mainly associated with decreased alkaline phosphatase (ALP) activity, whereas inhibition of JNK by SP600125 was associated with a marked reduction in osteocalcin (OC) production induced by BMP‐2. Corresponding alterations in ALP and OC mRNA levels were found in cells treated with BMP‐2 and inhibitors, suggesting an implication of p38 and JNK pathways in BMP‐2‐induced osteoblastic cell differentiation at a transcriptional level.
Conclusion: Data presented in this study describe p38 and JNK as new signaling pathways involved in BMP‐2‐induced osteoblastic cell differentiation with evidences for a distinct role of each MAP kinase in the control of alkaline phosphatase and osteocalcin expression.
We present a pooled analysis of predictive and prognostic values of circulating tumour cells (CTC) and circulating endothelial cells (CEC) in two prospective trials of patients with inflammatory ...breast cancer (IBC) treated with neoadjuvant chemotherapy combined with neoadjuvant and adjuvant bevacizumab.
Nonmetastatic T4d patients were enrolled in two phase II multicentre trials, evaluating bevacizumab in combination with sequential neoadjuvant chemotherapy of four cycles of FEC followed by four cycles of docetaxel in HER2-negative tumour (BEVERLY-1) or docetaxel and trastuzumab in HER2-positive tumour (BEVERLY-2). CTC and CEC were detected in 7.5 and 4ml of blood, respectively, with the CellSearch System.
From October 2008 to September 2010, 152 patients were included and 137 were evaluable for CTC and CEC. At baseline, 55 patients had detectable CTC (39%). After four cycles of chemotherapy, a dramatic drop in CTC to a rate of 9% was observed (P<0.01). Pathological complete response (pCR) rate was 40%. No correlation was found between CTC or CEC levels and pCR rate. Median follow-up was 43 months. CTC detection (≥1 CTC/7.5ml) at baseline was associated with shorter 3-year disease-free survival (39% versus 70% for patients without CTC, P<0.01, HR 2.80) and shorter 3-year overall survival (OS) (P<0.01). In multivariate analysis, independent prognostic parameters for shorter survival were absence of hormonal receptors, no pCR and CTC detection at baseline. CEC level at baseline or variations during treatment had no prognostic value.
In this pooled analysis of two prospective trials in nonmetastatic IBC, detection rate of CTC was 39% with a strong and independent prognostic value for survival. Combination of pCR after neoadjuvant treatment with no CTC detection at baseline isolated a subgroup of IBC with excellent OS (94% 3-year OS), suggesting that CTC count could be part of IBC stratification in prospective trials.
Inflammatory breast cancer (IBC) is a rare and aggressive disease requiring a multimodal treatment. We evaluated the benefit of adding docetaxel–5-fluorouracil (D-5FU) regimen after preoperative ...dose-intense (DI) epirubicin–cyclophosphamide (EC) and locoregional treatment in IBC patients.
PEGASE 07 was a national randomized phase III open-label study involving 14 hospitals in France. Women with nonmetastatic IBC were eligible and randomly assigned to receive either four cycles of DI EC (E 150 mg/m2 and C 4000 mg/m2 every 3 weeks with repeated hematopoietic stem cell support), then mastectomy with axillary lymph node dissection, and radiotherapy (arm A) or the same treatment followed by four cycles of D-5FU (D 85 mg/m2, day 1 and 5FU 750 mg/m2/day continuous infusion, days 1–5 every 3 weeks) administered postradiotherapy (arm B). Patients with hormone receptor-positive tumors received hormonal therapy. Disease-free survival (DFS) was the primary end point. Secondary end points included tolerance, pathological complete response (pCR) rate, and overall survival (OS).
Between January 2001 and May 2005, 174 patients were enrolled and treated (87 in each arm). Median follow-up was similar in both arms: 59.6 months 95% confidence interval (CI) 58.4–60.3 in arm A and 60.5 months (95% CI 58.3–61.4) in arm B. The estimated 5-year DFS rates were not different: 55% (95% CI 43.9–64.7) in arm A and 55.5% (95% CI 44.3–65.3) in arm B hazard ratio (HR) = 0.94 (0.61–1.48); P = 0.81. Identical results were observed for 5-year OS: 70.2% (95% CI 59.1–78.8) in arm A and 70% (95% CI 58.8–78.7) in arm B HR = 0.93 (0.55–1.60); P = 0.814. Following DI EC induction, in-breast and global (breast plus nodes) pCR were 28.9% and 20.1%, respectively. Estrogen receptor and pCR status were independently associated with survival.
The addition of D-5FU after preoperative DI EC and standard local therapy did not improve DFS in IBC.
ClinicalTrials.gov identifier: NCT02324088.
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