PAM50 Intrinsic Subtype Profiles in Primary and Metastatic Breast Cancer Show a Significant Shift toward More Aggressive Subtypes with Prognostic Implications

Background: PAM50 breast cancer intrinsic subtyping adds prognostic information in early breast cancer; however, the role in metastatic disease is unclear. We aimed to identify PAM50 subtypes in primary tumors (PTs) and metastases to outline subtype changes and their prognostic role. Methods: RNA was isolated from PTs, lymph node metastases (LNMs), and distant metastases (DMs) in metastatic breast cancer patients (n = 140) included in a prospective study (NCT01322893). Gene expression analyses were performed using the Breast Cancer 360 (BC360) assay from Nano-String. The subtype shifts were evaluated using McNemar and symmetry tests, and clinical outcomes were evaluated with log-rank tests and Cox regression. Results: The PAM50 subtype changed in 25/59 of paired samples between PTs and LNMs (Psymmetry = 0.002), in 31/61 between PTs and DMs (Psymmetry < 0.001), and in 16/38 between LNMs and DMs (Psymmetry = 0.004). Shifts toward subtypes with worse outcomes were the most common. Patients with shifts from the luminal PT to non-luminal DM subtypes had worse progression-free survival compared to patients with a stable subtype (hazard ratio (HR): 2.3; 95% confidence interval (CI): 1.14–4.68, p = 0.02). Conclusion: Strong evidence of PAM50 subtype shifts toward unfavorable subtypes were seen between PTs and metastatic samples. For patients with a shift in subtype from luminal PT to non-luminal DM, a worse prognosis was noted.

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Diagnostic, prognostic, and treatment monitoring value of plasma X in patients with metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.26_suppl.37 ◽

2014 ◽

Vol 32 (26_suppl) ◽

pp. 37-37

Author(s):

Cike Peng ◽

Rongxi Yang ◽

Dharanija Madhavan ◽

Markus Wallwiener ◽

Anja Rudolph ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cox Regression ◽

Metastatic Breast ◽

Progression Free Survival ◽

Fold Increase ◽

Base Line ◽

Breast Cancer Patients ◽

Free Survival ◽

Independent Cohort

37 Background: Metastasis is the main course of death in breast cancer (BC) patients. Reliable prognostic markers are very much appreciated to evaluate possible outcome of patients. Circulating tumor cells (CTC) is a circulating prognostic tumor marker of metastatic breast cancer patients. Despite the big technical challenges in CTC detection, the reliability of CTC enumeration for the prognosis of BC is still on debate. Some studies have proved that the plasma level of X, a major component in extracellular matrix, was increased in patients with metastatic breast cancer. However, the association between the plasma X level and the prognosis of metastatic breast cancer is still unknown. Methods: Plasma X was measured by ELISA in 60 healthy controls, 48 primary breast cancer (PBC) patients, and 212 metastatic breast cancer (MBC) patients. Progression free survival (PFS) and overall survival (OS) were analyzed. An independent cohort with 210 primary and 69 patients with metastatic breast cancer were further investigated to validate our findings. Results: A 2-fold elevation was presented in MBC patients when compared with PBC patients and controls, regardless of their CTC status. A multivariate Cox regression demonstrated that lower X level at base line was associated with longer PFS (HR: 2.50, 95% CI: 1.72–3.63, p = 1.607 × 10-6), as well as longer OS (HR: 3.74, 95% CI: 1.65 – 8.51, p = 0.002). After 1stcycle of chemotherapy, plasma X level was still prognostic and was dramatically decreased in patients who had responded to the treatment (54%, IQR: 36%–64%). In the independent validation round, a 2-fold increase of plasma X was observed again in MBC patients, compared with PBC patients. The prognostic value was also validated for PFS (HR: 2.12, 95% CI: 1.43– 3.84, p = 0.001) and OS (HR: 2.91, 95% CI: 1.73–7.65, p = 0.002) in MBC patients. Conclusions: Plasma X could be used as a diagnostic and prognostic marker for metastatic breast cancer. Its reduction after 1st cycle of chemotherapy could be an indicator of treatment efficacy. This finding may further prevent unnecessary systemic therapy by facilitating personalized medicine in the treatment of metastatic breast cancer.

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CTCs Expression Profiling for Advanced Breast Cancer Monitoring

Cancers ◽

10.3390/cancers11121941 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1941 ◽

Cited By ~ 2

Author(s):

Thais Pereira-Veiga ◽

Mónica Martínez-Fernández ◽

Carmen Abuin ◽

Roberto Piñeiro ◽

Victor Cebey ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Molecular Characterization ◽

Metastatic Breast ◽

Clinical Information ◽

Progression Free Survival ◽

Breast Cancer Patients ◽

Prognostic Information ◽

Enrichment Protocol ◽

Clinical Interest

The study of circulating tumor cells (CTCs) has a huge clinical interest in advance and metastatic breast cancer patients. However, many approaches are biased by the use of epithelial markers, which underestimate non-epithelial CTCs phenotypes. CTCs enumeration provides valuable prognostic information; however, molecular characterization could be the best option to monitor patients throughout the disease since it may provide more relevant clinical information to the physicians. In this work, we aimed at enumerating and performing a molecular characterization of CTCs from a cohort of 20 patients with metastatic breast cancer (MBC), monitoring the disease at different time points of the therapy, and at progression when it occurred. To this end, we used a CTC negative enrichment protocol that allowed us to recover a higher variety of CTCs phenotypes. With this strategy, we were able to obtain gene expression data from CTCs from all the patients. In addition, we found that high expression levels of PALB2 and MYC were associated with a worse outcome. Interestingly, we identified that CTCs with an EpCAMhighVIMlowALDH1A1high signature showed both shorter overall survival (OS) and progression-free survival (PFS), suggesting that CTCs with epithelial-stem features had the most aggressive phenotype.

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Survival impact of primary tumor resection in de novo metastatic breast cancer patients (GEICAM/El Alamo Registry)

Scientific Reports ◽

10.1038/s41598-019-55765-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Sara Lopez-Tarruella ◽

M. J. Escudero ◽

Marina Pollan ◽

Miguel Martín ◽

Carlos Jara ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Patients ◽

Primary Tumor ◽

Cox Regression ◽

De Novo ◽

Histological Grade ◽

Tumor Resection ◽

Metastatic Breast ◽

Breast Cancer Patients

AbstractThe debate about surgical resection of primary tumor (PT) in de novo metastatic breast cancer (MBC) patients persists. We explored this approach’s outcomes in patients included in a retrospective registry, named El Álamo, of breast cancer patients diagnosed in Spain (1990–2001). In this analysis we only included de novo MBC patients, 1415 of whom met the study’s criteria. Descriptive, Kaplan-Meier and Cox regression analyses were carried out. Median age was 63.1 years, 49.2% of patients had single-organ metastasis (skin/soft tissue [16.3%], bone [33.8%], or viscera [48.3%]). PT surgery (S) was performed in 44.5% of the cases. S-group patients were younger, had smaller tumors, higher prevalence of bone and oligometastatic disease, and lower prevalence of visceral involvement. With a median follow-up of 23.3 months, overall survival (OS) was 39.6 versus 22.4 months (HR = 0.59, p < 0.0001) in the S- and non-S groups, respectively. The S-group OS benefit remained statistically and clinically significant regardless of metastatic location, histological type, histological grade, hormone receptor status and tumor size. PT surgery (versus no surgery) was associated with an OS benefit suggesting that loco-regional PT control may be considered in selected MBC patients. Data from randomized controlled trials are of utmost importance to confirm these results.

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Methallotionein expression and outcome in patients with metastatic breast cancer (MBC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.1085 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 1085-1085

Author(s):

Jorge Arturo Rios-Perez ◽

Sameem Abedin ◽

Margaret Quinn Rosenzweig ◽

Su Yon Jung ◽

Rohit Bhargava ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Metastatic Breast ◽

Progression Free Survival ◽

Breast Cancer Diagnosis ◽

Rank Test ◽

Cancer Tissue ◽

Breast Cancer Patients ◽

Development Of Resistance ◽

Bivalent Metal Ions

1085 Background: Platinum-based agents are important components of therapy of metastatic breast cancer (MBC) and triple negative breast cancer. Their use can be limited by development of resistance. Metallothioneins (MT) are low molecular weight proteins believed to bind bivalent metal ions such as platinum and zinc. MT expression has been associated with decreased survival in breast cancer patients. A proposed mechanism confers resistance to platinum-based agents by their inactivation or limitation of their activity by MT binding. Methods: MT expression in 99 women with MBC (selected at random from our database of 800 women with MBC) was determined from primary breast cancer tissue (n=80) or metastatic tissue n=19). MT expression was determined by immunohistochemistry, and graded as negative, weak, moderate or strong. Clinical data was obtained through our database and supplemented by chart review. Overall survival from breast cancer diagnosis (OS), progression free survival for first metastastic regimen (PFS), and time from first metastasis to death or last update (metastatic survival, MS), were calculated through December 2011 using the log rank test. Results: Consistent with prior studies, moderate to strong MT expression was associated with decreased 5-year OS (p=.03). There was no correlation between MT expression and PFS or MS in this cohort. Surprisingly, MT expression at any degree was strongly associated with better MS in patients with MBC that received carboplatin-based regimens in the first line (n=25, p=.0005) or at any line (n=41, p=.0437). Conclusions: Consistent with prior studies, MT expression was associated with decreased survival in patients with MBC. Surprisingly, MT expression was associated with longer MS in patients with MBC that received carboplatin. These findings are inconsistent with the hypothesis that MT expression causes chemoresistance to platinum based agents in patients with metastatic breast cancer. Further studies are needed to elucidate the mechanisms behind these findings.

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Prospective Analysis of Patients with Metastatic Breast Cancer receiving Eribulin Mesylate as Second or More Lines of Chemotherapy: An Indian Experience

Clinical Medicine Insights Oncology ◽

10.1177/1179554918782475 ◽

2018 ◽

Vol 12 ◽

pp. 117955491878247 ◽

Cited By ~ 1

Author(s):

BJ Srinivasa ◽

Bhanu Prakash Lalkota ◽

Girish Badarke ◽

Diganta Hazarika ◽

Nasiruddin Mohammad ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Treatment Options ◽

Metastatic Breast ◽

Progression Free Survival ◽

Microtubule Inhibitor ◽

Eribulin Mesylate ◽

Primary Tumors ◽

Free Survival ◽

Heavily Pretreated

Background: Eribulin mesylate is a non-taxane microtubule inhibitor which can be used after anthracycline and taxane treatment in patients with metastatic breast cancer (MBC). The purpose of this study was to investigate the efficacy and safety of eribulin monotherapy in heavily pretreated patients with MBC. Methods: In this study, a total of 45 eligible patients with MBC who received eribulin in HCG Cancer Speciality Center from November 2014 to March 2016 were prospectively analyzed. Breslow (generalized Wilcoxon) survival analysis was carried out for progression-free survival and for overall survival. Patients were excluded if they had not taken treatment for 3 cycles and defaulted/expired during the treatment. Results: In this study, median age of patients was 52 years. A total of 27 (60%) patients had estrogen receptor and progesterone receptor (PR) positive primary tumors, whereas HER2 was overexpressed or amplified in 7 (15.6%); a triple negative subtype was recorded in 13 patients (28.9%). Regarding toxicity, 30 patients (66.67%) tolerated treatment well and 3 patients (6.67%) got anemia, 6 patients (13.3%) experienced neutropenia, and 7 (15.62%) patients had neurological toxicity. About 14 (31.1%) patients showed PR, 12 (26.7%) patients had stable disease (SD), whereas 19 (42.25%) patients showed progression disease (PD). Response evaluation at 6 cycles was possible in 18 patients and revealed that 4 (22.5%) patients showed PR, 10 (55.5%) patients had SD, whereas 4 (22.2%) patients had PD. Progression-free survival of the overall study population was 3.95 months. Conclusions: Eribulin mesylate is efficacious and tolerable chemotherapy as second- and third-line treatment options for MBC.

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Efficacy and Safety of Eribulin in Taxane-Refractory Patients in the “Real World”

10.20944/preprints201609.0093.v1 ◽

2016 ◽

Author(s):

Vito Lorusso ◽

Saverio Cinieri ◽

Agnese Latorre ◽

Luca Porcu ◽

Lucia Del Mastro ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Metastatic Breast ◽

Progression Free Survival ◽

Complete Response ◽

Breast Cancer Patients ◽

Peripheral Neurotoxicity ◽

Eribulin Mesylate ◽

Free Survival ◽

Toxic Drugs

Taxanes have been shown to be the most effective treatment for recurrent or metastatic breast cancer. However, for patients pretreated with taxanes, more active and possibly less toxic drugs are needed. In this retrospective study, we investigated on the effectiveness and safety of eribulin mesylate in 91 taxane-refractory subjects, extracted from the ESEMPIO database, which included 497 metastatic breast cancer patients treated with eribulin allover the Italy. This analysis included only those patients who have shown disease progression while receiving taxane therapy (primary refractory), or those who achieved a response followed by progression while still on therapy (taxane failure). Overall, 41/91 patients (45.2%) showed a clinical benefit; 1 complete response (2.2%) and 16 partial responses (17.6%) were observed. The median progression free survival was 3.1 months (95% CI: 2.8–3.5) and the median overall survival was 11.6 months (95% CI: 8.7–16.7). With regard to toxicity, 53 patients (58%) experienced asthenia/fatigue, 23 (25%) showed peripheral neurotoxicity, 18 (20%) alopecia, 12 (13%) mild constipation and 27 (30%) neutropenia. The toxicity related to the treatment led to eribulin dose reduction in 19 (21%) and discontinuation in 9 (10%) patients, respectively. In conclusion, this study suggests that eribulin is effective and well tolerated also in taxane-refractory patient.

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IL-6 is differentially expressed in the tumors of breast cancer patients treated with trastuzumab.

10.31219/osf.io/pcmnt ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Cancer Patients ◽

Messenger Rna ◽

Growth Factor Receptor ◽

Metastatic Breast ◽

The United States ◽

Differentially Expressed ◽

Breast Cancer Patients ◽

Primary Tumors

Trastuzumab (Herceptin) is a monoclonal antibody targeting the extracellular domain of the human epidermal growth factor receptor 2 (HER2) (1) utilized for the treatment of adjuvant and metastatic breast cancer (2) in the United States and worldwide. We mined published microarray and gene expression data (3, 4) to discover in an unbiased manner the most striking transcriptional features of trastuzumab treatment. We identified the cytokine interleukin-6 (IL-6) (5) as among the genes most differentially expressed in the primary tumors of patients with breast cancer treated with trastuzumab. The primary tumors of breast cancer patients treated with trastuzumab expressed higher levels of IL-6 messenger RNA than did patients not treated with trastuzumab, and a single administration of trastuzumab was sufficient to result in differential expression of IL-6 in primary tumors of the breast, suggesting that increased primary tumor expression of IL-6 in the primary tumors of patients with breast cancer, a cytokine whose serum levels are correlated with worse patient survival outcomes in metastatic breast cancer (6), is a direct transcriptional result of treatment with trastuzumab.

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Randomized phase-II evaluation of letrozole plus dasatinib in hormone receptor positive metastatic breast cancer patients

npj Breast Cancer ◽

10.1038/s41523-019-0132-8 ◽

2019 ◽

Vol 5 (1) ◽

Cited By ~ 3

Author(s):

Devchand Paul ◽

Svetislava J. Vukelja ◽

Frankie Ann Holmes ◽

Joanne L. Blum ◽

Kristi J. McIntyre ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Phase Ii ◽

Kinase Inhibitor ◽

Acquired Resistance ◽

Metastatic Breast ◽

Progression Free Survival ◽

Therapy Resistance ◽

Breast Cancer Patients ◽

Er Positive

Abstract The non-receptor tyrosine kinase Src activation plays a role in the malignant progression of breast cancer, including development of endocrine therapy resistance and survival of bone metastases. This study investigated whether adding Src kinase inhibitor dasatinib to aromatase inhibitor (AI) therapy improved outcomes in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (MBC). Postmenopausal patients with ER-positive, HER2-negative MBC (0–1 prior chemotherapies and no prior AI for MBC) were eligible for this non-comparative, parallel group, phase-II study. Patients were randomized to letrozole (2.5 mg/day PO) alone or with dasatinib (100 mg/day PO). Patients with disease progression on letrozole alone could crossover to dasatinib plus continued letrozole. The primary endpoint was clinical-benefit-rate (CBR; complete response + partial response + stable disease ≥6 months). A total of 120 patients were randomized. The CBR of 71% (95% CI 58–83%) was observed with letrozole + dasatinib versus the projected CBR of the combination of 56%. The CBR of 66% (95% CI 52–77%) with letrozole alone also exceeded the projected CBR of 39% with letrozole alone. The CBR was 23% in the crossover arm of letrozole plus dasatinib in patients progressing on letrozole alone. Median progression-free survival with the combination was 20.1 months and 9.9 months with letrozole alone. Letrozole plus dasatinib was well tolerated, although 26% of patients required dasatinib dose reductions. In this non-comparative phase-II trial, the CBR of 71% and the median PFS of 20.1 months with letrozole + dasatinib are encouraging and suggest that dasatinib may inhibit the emergence of acquired resistance to AI therapy.

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Epithelial/Mesenchymal Characteristics and PD-L1 Co-Expression in CTCs of Metastatic Breast Cancer Patients Treated with Eribulin: Correlation with Clinical Outcome

Cancers ◽

10.3390/cancers12123735 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3735

Author(s):

Hara Polioudaki ◽

Anastasia Mala ◽

Eleni Gkimprixi ◽

Maria A. Papadaki ◽

Amanda Chantziou ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Mononuclear Cells ◽

Cox Regression ◽

Metastatic Breast ◽

Breast Cancer Patients ◽

Peripheral Blood Mononuclear ◽

Cox Regression Analysis ◽

Risk Of Death ◽

Increased Risk

We aimed to evaluate the co-expression of PD-L1 and epithelial-mesenchymal markers in CTCs from metastatic breast cancer (MBC) patients and to determine if there is any relationship with patients’ outcome after eribulin treatment. Using cytospin preparations of peripheral blood mononuclear cells (PBMCs) from MBC patients treated with eribulin and a combination of immunocytochemistry and immunofluorescence, we quantified PD-L1, keratins and vimentin in single and cluster CTCs on days 1 and 8 of the first-treatment cycle. CTCs (n = 173) were found in 31 out of 38 patients. At baseline, the presence of cluster CTCs (p = 0.048), cluster mesenchymal CTCs (mCTCs) (p = 0.0003) or cluster PD-L1+mCTCs (p = 0.006) was associated with shorter overall survival (OS). In multivariate cox regression analysis, the detection of cluster mCTCs was the only parameter associated with increased risk of death (p = 0.024). On day 8 post-eribulin administration, PD-L1+mCTCs and especially single PD-L1+mCTCs decreased in 75% and 89% of patients, respectively. The detection of single PD-L1+mCTCs after eribulin treatment was correlated with shorter PFS (p = 0.047) and OS (p = 0.020). In conclusion, our study identified for the first time that cluster and single PD-L1+mCTCs subpopulations are of clinical significance in patients with MBC and highlighted the importance of CTC phenotyping during treatment with eribulin.

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Factors associated with mortality after breast cancer metastasis.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.27_suppl.174 ◽

2011 ◽

Vol 29 (27_suppl) ◽

pp. 174-174

Author(s):

S. Y. Jung ◽

M. Q. Rosenzweig ◽

S. M. Sereika ◽

F. Linkov ◽

A. Brufsky ◽

...

Keyword(s):

Breast Cancer ◽

Prognostic Factors ◽

Metastatic Breast Cancer ◽

Cancer Patients ◽

Cancer Metastasis ◽

Cox Regression ◽

Metastatic Breast ◽

Breast Cancer Metastasis ◽

Her2 Status ◽

Breast Cancer Patients

174 Background: It is generally accepted that patients with breast cancer metastases have poor survival. Metastatic breast cancer patients can be considered a heterogeneous population with a varied clinical course, which underscores the need for accurate prediction of survival based on prognostic factors. The purpose of the present study was to identify factors related to survival in breast cancer patients after diagnosis with metastatic disease. Methods: A total of 557 patients with breast cancer metastasis diagnosis seen at one large urban practice have been followed up between January 1, 1999 and June 30, 2008. Demographic, tumor characteristics, clinical factors as predictors of survival were analyzed using Cox regression model. Results: The median survival length was 40 months (range 1-114 months) with 269 (48.3%) alive and 288 (51.7%) dead. This study demonstrated that hypertension, estrogen receptor (ER) and/or progesterone receptor (PR) status, human epidermal growth factor receptor-2 (HER2) status, number of metastatic sites, and body mass index (BMI) at diagnosis with metastatic breast cancer were the most relevant prognostic factors for survival after metastasis. Conclusions: Findings of this study may form a foundation for the corpus of knowledge explaining the outcome differences in treatment of patients with metastatic breast cancer, potentially helping to create tailored counseling and personalized treatment approaches for this vulnerable group. [Table: see text]

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