Effects of neoadjuvant trastuzumab, pertuzumab and palbociclib on Ki67 in HER2 and ER-positive breast cancer

The crosstalk between estrogen and HER2 receptors and cell-cycle regulation sustains resistance to endocrine therapy of HER2- and hormone receptor-positive breast cancer. We earlier reported that women with HER2 and ER-positive breast cancer receiving neoadjuvant dual HER2-block and palbociclib in the NA-PHER2 trial had Ki67 decrease and 27% pathological complete responses (pCR). We extended NA-PHER2 to Cohort B using dual HER2-block and palbociclib without fulvestrant and report here Ki67 drops at week-2 (mean change −25.7), at surgery (after 16 weeks, mean change −9.5), high objective response (88.5%) and pCR (19.2%). In Cohort C [Ki67 > 20% and HER2low (IHC 1+/2+ without gene amplification)], women also received fulvestrant, had dramatic Ki67 drop at week 2 (−29.5) persisting at surgery (−19.3), and objective responses in 78.3%. In view of the favorable tolerability and of the efficacy-predictive value of Ki67 drop at week-2, the chemotherapy-free approach of NA-PHER2 deserves further investigation in HER2 and ER-positive breast cancer. The trial is registered with ClinicalTrials.gov, number NCT02530424.

Programmed Death-Ligand 1 (PD-L1) as Immunotherapy Biomarker in Breast Cancer

Breast cancer constitutes the most common malignant neoplasm in women around the world. Approximately 12% of patients are diagnosed with metastatic stage, and between 5 and 30% of early or locally advanced BC patients will relapse, making it an incurable disease. PD-L1 ligation is an immune inhibitory molecule of the activation of T cells, playing a relevant role in numerous types of malignant tumors, including BC. The objective of the present review is to analyze the role of PD-L1 as a biomarker in the different BC subtypes, adding clinical trials with immune checkpoint inhibitors and their applicable results. Diverse trials using immunotherapy with anti-PD-1/PD-L1 in BC, as well as prospective or retrospective cohort studies about PD-L1 in BC, were included. Despite divergent results in the reviewed studies, PD-L1 seems to be correlated with worse prognosis in the hormone receptor positive subtype. Immune checkpoints inhibitors targeting the PD-1/PD-L1 axis have achieved great response rates in TNBC patients, especially in combination with chemotherapy, making immunotherapy a new treatment option in this scenario. However, the utility of PD-L1 as a predictive biomarker in the rest of BC subtypes remains unclear. In addition, predictive differences have been found in response to immunotherapy depending on the stage of the tumor disease. Therefore, a better understanding of tumor microenvironment, as well as identifying new potential biomarkers or combined index scores, is necessary in order to make a better selection of the subgroups of BC patients who will derive benefit from immune checkpoint inhibitors.

Treatment Exposure and Discontinuation in the PALbociclib CoLlaborative Adjuvant Study of Palbociclib With Adjuvant Endocrine Therapy for Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Early Breast Cancer (PALLAS/AFT-05/ABCSG-42/BIG-14-03)

PURPOSE The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS. METHODS Patients with stage II-III HR+, HER2– disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS. RESULTS Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non–protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11). CONCLUSION Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.

Clinical Progress of PD-1/L1 Inhibitors in Breast Cancer Immunotherapy

Breast cancer is a major killer of women’s health worldwide. While breast cancer is thought to have lower immunogenicity compared with other solid tumors, combination therapy is able to improve the immunogenicity of the tumor and sensitize breast cancer cells to immunotherapy. Immunotherapy represented by immune checkpoint inhibitors (ICIs) has been largely explored in the field of breast cancer, including both early and advanced disease. Immunotherapy for triple-negative breast cancer (TNBC) has been the most studied, and the PD-L1 inhibitor atezolizumab combined with nab-paclitaxel has been used in the first-line treatment of TNBC. Immunotherapeutic data for human epidermal growth factor receptor-positive and hormone receptor-positive breast cancer are also accumulating. This review summarizes the clinical trial data of ICIs or ICI-containing therapies in different types and stages of breast cancer.

Neoadjuvant Therapy with Doxorubicin-Cyclophosphamide Followed by Weekly Paclitaxel in Early Breast Cancer: A Retrospective Analysis of 200 Consecutive Patients Treated in A Single Center with A Median Follow-Up of 9.5 Years.

Purpose We analyzed outcomes of doxorubicin-cyclophosphamide(AC) followed by weekly paclitaxel as neoadjuvant chemotherapy(NAC) for breast cancer(BC), in an everyday practice with long-term follow-up of patients. Methods All patients (n=200) who received the AC-paclitaxel combination as NAC for BC at the Soroka University Medical Center from 2003 to 2012 were included in this retrospective cohort study. AC was administered on an every 3-week schedule (standard dose) until May, 2007(n=99); and subsequently every 2 weeks (dose dense)(dd)(n=101). Clinical pathologic features, treatment course and outcome information were recorded. Complete pathologic response(pCR) was analyzed according to BC subtype, dose regimen and stage. Results Median age was 49 years; 55.5% and 44.5% of patients were clinically stage 2 and 3, respectively. Standard dose patients had more T3 tumors. Subtypes were human-epidermal-growth-factor receptor(HER 2)-positive 32.5% (of whom 82% received trastuzumab), hormone-receptor positive/HER2 negative 53%, triple negative 14.5%. Breast conserving surgery(BCS) was performed in 48.5% of patients; only 9.5% were deemed suitable for BCS prior to NAC. Toxicity was acceptable. The overall pCR rate was 26.0% and was significantly higher in the dd group and HER2-positive patients. With a median follow-up of 9.51 years median event-free survival(EFS), and overall survival(OS) is 10.85 years and 12.61 years, respectively. Patients achieving pCR had significantly longer EFS and OS. Conclusions- NAC for BC with AC-paclitaxel can be safely administered in the “real-world’ setting with high efficacy. Current efforts are aimed at Increasing rates of pCR and identifying patients who may benefit from additional therapy or conversely, de-escalated treatment.

PTEN promoter methylation predicts 10-year prognosis in hormone receptor-positive early breast cancer patients who received adjuvant tamoxifen endocrine therapy

Purpose There remain a lack of biomarkers for endocrine therapy resistance in patients with breast cancer (BC), which is proving to be a great challenge. In vitro experiments have shown that downregulation of PTEN expression leads to resistance to tamoxifen (TAM) in BC cells. We aimed to investigate the predictive role of tumor PTEN promoter methylation and PTEN expression in long-term survival after TAM adjuvant therapy in patients with early-stage BC. Methods From 2001 to 2013, 105 patients with stage I–III BC who were treated with standardized adjuvant TAM for 5 years or until relapse in West China Hospital (WCH) were enrolled in this study. PTEN expression and DNA methylation of three specified sequences from the PTEN promoter in primary tumors were measured using immunohistochemistry and pyrosequencing. A cohort of 159 hormone receptor-positive patients receiving TAM treatment from The Cancer Genome Atlas (TCGA) database was used for verification. Results Median follow-up time for the WCH cohort was 141.7 months. The low, moderate, and high PTEN expression groups had differing 10-year disease-free survival (DFS) (42.3%, 55%, 81%, respectively, P = 0.027) and overall survival (OS) rates (65%, 84.2%, 90.5%, respectively, P = 0.027). Higher methylation levels of the second sequence (− 819 to − 787 bp), rather than the first (− 1143 to − 1107 bp) or third sequence (− 663 to − 593 bp), independently increased the risk of disease recurrence (hazard ratio = 2.60) and death (hazard ratio = 3.79) in the WCH cohort, according to multivariate Cox regression analysis. Importantly, out of the five CpG islands located within this sequence, only high methylation of the − 796 CpG island predicted shorter DFS and OS. In TCGA validation cohort, there was also a trend of higher methylation of the − 796 CpG island correlating with shorter disease-free intervals, with borderline significance (P = 0.057). Conclusion Low PTEN expression and high methylation of its promoter (sequence − 819 to − 787 bp) in tissue predict poor DFS and OS in hormone receptor-positive early BC patients who received adjuvant TAM.