Emerging new predictive biomarkers in metastatic breast cancer: Caveolin-1 and weekly nab-paclitaxel plus gemcitabine, are we on for tomorrow?

There are three US FDA–approved CDK4/6 inhibitors: palbociclib, ribociclib and abemaciclib for patients with HR-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (MBC). They are all equally effective, so the question becomes how to choose among these agents and how to sequence them. Other areas with active investigation include identifying predictive biomarkers for the selection of patients whom may benefit more from CDK4/6 inhibitors, deciding whether to continue CDK4/6 inhibitors after disease progression on CDK4/6 inhibitors, creating novel treatment combinations and expanding use beyond HR+/HER2- MBC. Here, we review the current use of and potential next directions for CDK4/6 inhibitors in the treatment of patients with HR+/HER2- MBC.

Download Full-text

Safety, efficacy, and biomarker analysis of pyrotinib in combination with capecitabine in HER2-positive metastatic breast cancer patients: A phase I clinical trial.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.1035 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 1035-1035

Author(s):

Fei Ma ◽

Qiao Li ◽

Xiuwen Guan ◽

Shanshan Chen ◽

Zongbi Yi ◽

...

Keyword(s):

Breast Cancer ◽

Clinical Trial ◽

Metastatic Breast Cancer ◽

Antitumor Activity ◽

Metastatic Breast ◽

Predictive Biomarkers ◽

Genetic Alterations ◽

Her2 Positive ◽

Blood Samples ◽

Grade 3

1035 Background: Cross-signaling in the ErbB family is an important mechanism in Trastuzumab resistance. Pyrotinib is an irreversible pan-ErbB inhibitor targeting EGFR/HER1, HER2 and HER4, which may offer the potential for improved efficacy to block HER2 signaling in trastuzumab-resistant breast cancer. This phase I study assessed the safety, tolerability, maximum-tolerated dose (MTD), pharmacokinetics, antitumor activity and predictive biomarkers of pyrotinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer (MBC). Methods: Patients received oral pyrotinib 160 mg, 240 mg, 320 mg, or 400 mg once daily continually plus capecitabine 1000mg/m2 twice daily on days 1 to 14 of a 21-day cycle. Pharmacokinetic blood samples were collected predose on day 1 and day 14 of treatment. Next-generation sequencing (NGS) was performed on circulating tumor DNA (ctDNA) to probe for predictive biomarkers of this combination. Results: A total of 28 patients were enrolled. All 28 (100%) patients experienced at least one treatment-related Adverse Events (AE), which were predominantly grade 1 or 2. Grade 3 treatment-related AE occurred in 12 (42.9%) patients; anemia (14.3%) and diarrhea (10.7%) were the most common grade 3 AEs. Three (10.7%) patients discontinued capecitabine administration due to AEs. The overall response rate (ORR) was 78.6% (95% CI: 59.0% to 91.7%), and the disease control rate (complete response+ partial response+ stable disease) was 96.4% (95% CI: 81.7% to 99.9%). The median progression-free survival (PFS) was 22.1 months (95% CI: 9.0 to 26.2 months). ORR was 70.6% (12/17) in trastuzumab-pretreated patients and 90.9% (10/11) in trastuzumab-naive patients. NGS analysis of all genetic alterations of HER2 bypass signaling pathway, PI3K/Akt/mTOR pathway and TP53 in baseline blood samples suggested that concomitant (two or more) genetic alterations were significantly associated with poorer PFS compared to none or one genetic alteration (median, 15.8 vs. 26.2 months, p = 0.006). Conclusions: Pyrotinib in combination with capecitabine are well-tolerated and demonstrate promising antitumor activity in HER2-positive MBC patients. Clinical trial information: NCT02361112.

Download Full-text

Serum NSE, MMP-9 and HER2 extracellular domain are associated with brain metastases in metastatic breast cancer patients: predictive biomarkers for brain metastases?

International Journal of Cancer ◽

10.1002/ijc.30290 ◽

2016 ◽

Vol 139 (10) ◽

pp. 2299-2311 ◽

Cited By ~ 9

Author(s):

Amélie Darlix ◽

Pierre-Jean Lamy ◽

Evelyne Lopez-Crapez ◽

Antoine Laurent Braccini ◽

Nelly Firmin ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Brain Metastases ◽

Cancer Patients ◽

Metastatic Breast ◽

Predictive Biomarkers ◽

Extracellular Domain ◽

Breast Cancer Patients

Download Full-text

Determination of the androgen receptor status of circulating tumour cells in metastatic breast cancer patients

BMC Cancer ◽

10.1186/s12885-019-6323-8 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Natalia Krawczyk ◽

Melissa Neubacher ◽

Franziska Meier-Stiegen ◽

Hans Neubauer ◽

Dieter Niederacher ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Androgen Receptor ◽

Cell Lines ◽

Metastatic Breast ◽

Predictive Biomarkers ◽

Tumour Cells ◽

Her2 Status ◽

Circulating Tumour Cells ◽

Breast Cancer Patients

Abstract Background The prognostic relevance of circulating tumour cells (CTCs) in metastatic breast cancer (MBC) patients has been confirmed by several clinical trials. However, predictive blood-based biomarkers for stratification of patients for targeted therapy are still lacking. The DETECT studies explore the utility of CTC phenotype for treatment decisions in patients with HER2 negative MBC. Associated with this concept is a plethora of translational projects aiming to identify potential predictive biomarkers. The androgen receptor (AR) is expressed in over 70% of hormone receptor-positive and up-to 45% of triple-negative tumours. Studies has indicated the promising nature of AR as a new therapy target with a clinical benefit rate for anti-AR treatment in MBC patients up to 25% The aim of this analysis was the characterization of CTCs regarding the expression of the AR using immunofluorescence. Methods MBC patients were screened for the HER2-status of CTCs in the DETECT studies. In a subset of CTC-positive patients (n = 67) an additional blood sample was used for immunomagnetic enrichment of CTCs using the CellSearch® Profile Kit prior to transfer of the cells onto cytospin slides. Establishment of immunofluorescence staining for the AR was performed using prostate cancer cell lines LNCaP and DU145 as positive and negative control, respectively. Staining of DAPI, pan-cytokeratin (CK) and CD45 was applied to identify nucleated epithelial cells as CTCs and to exclude leucocytes. Results Co-staining of the AR, CK and CD45 according to the above mentioned workflow has been successfully established using cell lines with known AR expression spiked into the blood samples from healthy donors. For this translational project, samples were analysed from 67 patients participating in the DETECT studies. At least one CTC was detected in 37 out of 67 patients (56%). In 16 of these 37 patients (43%) AR-positive CTCs were detected. In eight out of 25 patients (32%) with more than one CTC, AR-positive and AR-negative CTCs were observed. Conclusion In 43% of the analysed CTC samples from patients with MBC the AR expression has been detected. The predictive value of AR expression in CTCs remains to be evaluated in further trials.

Download Full-text

The Use of Immunotherapy to Treat Metastatic Breast Cancer

Current Medicinal Chemistry ◽

10.2174/0929867325666180209124052 ◽

2019 ◽

Vol 26 (6) ◽

pp. 941-962 ◽

Cited By ~ 8

Author(s):

Andrea Nicolini ◽

Vivian Barak ◽

Piermario Biava ◽

Paola Ferrari ◽

Giuseppe Rossi ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Immune Modulation ◽

Molecular Subtypes ◽

Immune Therapy ◽

Metastatic Breast ◽

Predictive Biomarkers ◽

Phase Iii ◽

First Line ◽

Her2 Positive

This article reviews the principal attempts of immune-modulation or immune therapy in metastatic breast cancer. It considers their rationale and reports on results from the relevant key clinical trials. Immune-modulatory or immune-stimulating cytokines used alone or combined with conventional therapies is among the principal approaches of immune manipulation in breast cancer. As this issue has recently been reviewed by us, the aim of the current article is to discuss our updated and unpublished data on this topic. Overall survival in luminal (28 patients) and non-luminal (9 patients) molecular subtypes is 91 and 59 months respectively that is about two and half or three times longer than expected. Thereafter, we focus on monoclonal antibodies (mAb) based-therapies including novel strategies to overcome resistance to anti-HER2 mAb. The main vaccine platforms in different molecular subtypes and immune therapies in triple negative metastatic breast cancer (m-TNBC) are discussed in the last sections. Some phase III investigations have already changed the current clinical practice. In fact, pertuzumab plus trastuzumab and docetaxel is the recommended first line regimen in HER2 positive locally recurrent or metastatic breast cancer and bevacizumab plus paclitaxel or docetaxel is a reasonable option for m-TNBC. In some other observational or phase I/II studies on first-line trastuzumab plus chemotherapy and hormonal therapy and in that on HER2 peptide/protein vaccines promising although preliminary findings have been reported to be further validated. In the remaining studies, results were disappointing. In the future, finding new predictive biomarkers and exploring more suitable synergizing combinations, time and dose-dependent-scheduled sequences of currently and further investigated immunological approaches are main challenges.

Download Full-text