circulating tumor cells as a surrogate for response to treatment

[Rich66]

SAN DIEGO, Aug. 24, 2011 /PRNewswire
Biocept and Clarient Announce Collaboration on First Test for Circulating Tumor Cells and HER2 Status in Breast Cancer Patients

(Note: this is newer than other established CTC tests like cellsearch etc)

LINK

The OncoCEE-BR™ test includes enumeration of CTCs as well as the determination of HER2 status by FISH. Biocept intends to add ER/PR status determination to the test, and potentially other biomarkers, in the future. OncoCEE-BR™ is the only commercially available CTC test that combines enumeration and cytogenetic characterization.
Ron Andrews, CEO of Clarient, said, "Establishing the ability to perform molecular characterization of peripheral cancer cells from a blood sample takes us one step closer to making cancer a chronic disease. Biocept's OncoCEE™ platform supports our mission of personalized medicine and care for cancer patients."
Biocept's OncoCEE-BR™ test is expected to have application in several clinical settings, including:

• At the time of recurrence, and especially in cases where a biopsy may be difficult to obtain, to determine if the patient's HER2 status has changed from the original diagnosis or surgery.
• Confirmation of HER2 status at the time of original diagnosis or surgery, where tumor tissue analysis was negative for HER2 amplification. Biocept has demonstrated detection of HER2-amplified CTCs in patients with HER2 negative primary tumors, a finding reported by other groups in the scientific literature. This suggests that the pathologist may have examined a part of the tumor that was not HER2 amplified for a variety of reasons including tumor heterogeneity, and that treatment with HER2-targeted agents may be justified. This could be a life-changing event for a breast cancer patient.

(The following presumably based on traditional CTC tests before OncoCEE-BR)


Breast Cancer. 2009 Aug 1. [Epub ahead of print]
Multi-center study evaluating circulating tumor cells as a surrogate for response to treatment and overall survival in metastatic breast cancer.

Nakamura S, Yagata H, Ohno S, Yamaguchi H, Iwata H, Tsunoda N, Ito Y, Tokudome N, Toi M, Kuroi K, Suzuki E.
Department of Breast Surgical Oncology, St. Luke's International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo, 104-8560, Japan, seigonak@luke.or.jp.
BACKGROUND: Evaluating circulating tumor cells (CTCs) is one way to predict outcome and monitor treatment in patients with MBC. In this prospective study, we evaluated CTCs in predicting treatment efficacy and overall survival (OS) using the CellSearch System (Veridex, LLC, Raritan, NJ). METHODS: One hundred nineteen patients with MBC with measurable disease were enrolled. Samples of 7.5 ml of blood from 107 eligible patients were tested for CTCs before starting therapy (baseline), after one cycle of therapy (3-4 weeks) and at 12 weeks. We compared CTC levels and imaging at baseline and at 12 weeks. Next, we determined the hazard ratios (HR) by comparing cases with zero CTCs to those with one or more CTCs. Moreover, HR was calculated when comparing cases that had greater than or equal to a certain number of CTCs to those with less than the number of CTCs. RESULTS: This study shows the incidence of detection of CTCs in patients with metastatic breast cancers. Of the patients, 64.4% (76/118) had one or more CTCs, and 37.3% (44/118) had five or more CTCs. First we set the baseline number of CTCs as 100%. Of the seven cases whose level of CTCs decreased more than 90%, six (85.7%) demonstrated a positive response (complete response and partial response) by imaging after one cycle (3-4 weeks later). For the patients whose CTC levels increased above 100% after one cycle (3-4 weeks later), 7 of 11 (63.6%) had progressive disease (PD). The HR for cases with five to ten CTCs was greater than 1.00 [HR = 2.450; 95% confidence interval (CI) 0.727-8.248]. Statistical significance was observed when comparing patients who had >/=3 CTCs to those with <3 CTCs (P = 0.0273). When comparing cases with >/=5 CTCs to those with <5 CTCs, the hazard ratio was 3.069 (95% CI 1.496-6.295; P = 0.0022). CONCLUSIONS: Because the change in the number of CTCs was highly correlated with results from imaging before and after therapy, CTCs can be considered a biomarker that may predict the effect of treatment earlier than imaging modalities.

PMID: 19649686 [PubMed - as supplied by publisher]




Br J Cancer. 2012 Apr 19. doi: 10.1038/bjc.2012.157. [Epub ahead of print]
The dynamic change of circulating tumour cells in patients with operable breast cancer before and after chemotherapy based on a multimarker QPCR platform.

Chong MH, Zhao Y, Wang J, Zha XM, Liu XA, Ling LJ, Du Q, Wang S.

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Source

Department of Breast Surgery, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing 210029, China.

Abstract

Background:The possible presence of early tumour dissemination is the rationale behind the use of systemic adjuvant chemotherapy in patients with operable breast cancer. Circulating tumour cells (CTC) in peripheral blood may represent the possible presence of early tumour dissemination. However, relatively few studies were designed to investigate the relationship between the change of CTC status and the efficacy of adjuvant chemotherapy in operable breast cancer patients.
Methods: In a prospective study, we established a multimarker real-time quantitative PCR platform to detect CTC in peripheral blood of breast cancer patients. By using this platform, we detected CTC in peripheral blood of 94 operable breast cancer patients. Control group consisted of 20 patients with benign breast disease and 20 healthy volunteers. For 72 patients who underwent systemic adjuvant chemotherapy, the dynamic CTC status at three different time points (1 day before initiation of chemotherapy, 1 week after three cycles of chemotherapy and 1 week after all cycles of chemotherapy) was observed.
Results: Circulating tumour cells were detected in 56% (53 out of 94) of patients with operable breast cancer. The specificity was 95%. Seventy-two patients who received systemic adjuvant chemotherapy were followed up. After three cycles of chemotherapy, 47% (18 out of 38) of patients who were CTC-positive before chemotherapy changed into negative status. In addition, another 5% (2 out of 38) of patients had changed into negative status after all cycles of chemotherapy.
Conclusion: Systemic adjuvant chemotherapy had a significant impact on CTC status, and this effect could be observed after three cycles of chemotherapy. Circulating tumour cells detection had the potential to be used to evaluate the efficacy of systemic adjuvant chemotherapy immediately after the chemotherapy was finished in operable breast cancer patients.


British Journal of Cancer advance online publication, 19 April 2012; doi:10.1038/bjc.2012.157 www.bjcancer.com.

PMID:

22516945

[PubMed - as supplied by publisher]

British Journal of Cancer (2010) 102, 561 – 569
& 2010 Cancer Research UK All rights reserved 0007 – 0920/10 $32.00
www.bjcancer.com

Circulating tumour cells demonstrate an altered response to hypoxia and an aggressive phenotype
K Ameri*,1, R Luong2, H Zhang1, AA Powell1, KD Montgomery3, I Espinosa3, DM Bouley2, AL Harris4 and
SS Jeffrey*,1
1Department of Surgery Stanford University School of Medicine, Stanford, CA, USA; 2Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA, USA; 3Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; 4Department of Medical Oncology and Molecular Oncology Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

FULL PDF

BACKGROUND: Tumours contain hypoxic regions that select for an aggressive cell phenotype; tumour hypoxia induces metastasisassociated
genes. Treatment refractory patients with metastatic cancer show increased numbers of circulating tumour cells (CTCs), which are also associated with disease progression. The aim of this study was to examine the as yet unknown relationship between hypoxia and CTCs.
METHODS: We generated human MDA-MB-231 orthotopic xenografts and, using a new technology, isolated viable human CTCs from murine blood. The CTCs and parental MDA-MB-231 cells were incubated at 21 and 0.2% (hypoxia) oxygen, respectively. Colony formation was assayed and levels of hypoxia- and anoxia-inducible factors were measured. Xenografts generated from CTCs and parental cells were compared.

RESULTS: MDA-MB-231 xenografts used to generate CTCs were hypoxic, expressing hypoxia factors: hypoxia-inducible factor1 alpha (HIF1a) and glucose transporter protein type 1 (GLUT1), and anoxia-induced factors: activating transcription factor 3 and 4 (ATF3 and ATF4). Parental MDA-MB-231 cells induced ATF3 in hypoxia, whereas CTCs expressed it constitutively. Asparagine synthetase (ASNS) expression was also higher in CTCs. Hypoxia induced ATF4 and the HIF1a target gene apelin in CTCs, but not in parental cells. Hypoxia induced lower levels of carbonic anhydrase IX (CAIX), GLUT1 and BCL2/adenovirus E1B 19-KD protein-interacting protein 3 (BNIP3) proteins in CTCs than in parental cells, supporting an altered hypoxia response. In chronic hypoxia, CTCs demonstrated greater colony formation than parental cells. Xenografts generated from CTCs were larger and heavier, and metastasised faster than MDA-MB-231 xenografts.
CONCLUSION: CTCs show an altered hypoxia response and an enhanced aggressive phenotype in vitro and in vivo.
British Journal of Cancer (2010) 102, 561–569. doi:10.1038/sj.bjc.6605491 www.bjcancer.com
Published online 5 January 2010
& 2010 Cancer Research UK



J Cancer Res Clin Oncol. 2009 Apr;135(4):643-7. Epub 2008 Oct 21.
Monitoring circulating epithelial tumour cells (CETC) to gauge therapy: in patients with disease progression after trastuzumab persisting CETC can be eliminated by combined lapatinib treatment.

Camara O, Jörke C, Hammer U, Egbe A, Rabenstein C, Runnebaum IB, Hoeffken K, Pachmann K.
Women's Hospital, Friedrich Schiller University, Bachstr. 18, 07740, Jena, Germany.
BACKGROUND: In breast cancers, the gene for the growth factor receptor HER2 can be amplified leading to increased aggressiveness and metastasis formation. The monoclonal antibody trastuzumab prolongs relapse-free survival highly significantly but eventually many patients relapse. METHOD: In this study, CETC were monitored using the Maintrac method during adjuvant trastuzumab treatment and during subsequent treatment with capecitabine/lapatinib. RESULTS: In one patient, trastuzumab led to marginal reduction in CETC with disease progress. The combination of capecitabine/lapatinib was preliminarily capable to eliminate all CETC, however, CETC reappeared. The second patient received adjuvant taxane together with trastuzumab and 1 year of further trastuzumab during which CETC increased. After stopping trastuzumab skin metastases occurred. Capecitabine/lapatinib led to complete CETC elimination with stable disease. CONCLUSIONS: In patients with lack of CETC reduction in spite of trastuzumab treatment correlated with disease progression the combination of capecitabine/lapatinib highly efficiently led to rapid elimination of CETC warranting further monitoring during such studies.

PMID: 18936973 [PubMed - indexed for MEDLINE]



Eur J Cancer. 2008 Dec;44(18):2721-5. Epub 2008 Nov 18.
The direct molecular analysis of metastatic precursor cells in breast cancer: a chance for a better understanding of metastasis and for personalised medicine.

Klein CA.
Division of Oncogenomics, Department of Pathology, University of Regensburg, Regensburg, Germany. christoph.klein@klinik.uni-regensburg.de
The search for disseminated cancer cells has become a routine procedure in many clinical centres since the pioneering work of Riethmüller and Schlimok was published in the mid 1980s. Until today, clinical studies have mostly focused on the prognostic role of disseminated cancer cells that can be detected in bone marrow samples before manifestation of metastasis. As a more recent development, the field is increasingly concentrating on the prognostic information provided by tumour cells circulating in the peripheral blood instead of analysing the nature of disseminated tumour cells that have successfully homed to a new microenvironment and may eventually grow into metastases. This review critically questions that direction and proposes exploiting the unique opportunities provided by the direct molecular analysis of metastatic precursor cells for a better understanding of metastasis, tumour dormancy, therapy target identification, and personalised medicine in an adjuvant therapy setting.

PMID: 19022661 [PubMed - indexed for MEDLINE]