Helen Politaki

University of Crete

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Vassilis Georgoulias

Hellenic Oncology Research Group

Maria Tzardi

University Hospital of Heraklion

Alexandra Voutsina

University of Crete

E. Papadimitraki

University College London Hospitals NHS Foundation Trust

John Souglakos

University of Crete

Aristea Kalikaki

University of Crete

Stella Apostolaki

The American College of Greece

Alexios Matikas

Karolinska Institutet

Kostas Kalbakis

University Hospital of Heraklion

Maria Perraki

University of Crete

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University of Crete

University Hospital of Heraklion

Hellenic Oncology Research Group

National and Kapodistrian University of Athens

IASO General Hospital

Foundation for Research and Technology Hellas

Inova Alexandria Hospital

American Society of Clinical Oncology

Institut Jules Bordet

St Savas Hospital

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Detection of circulating tumour cells before and following adjuvant chemotherapy and long-term prognosis of early breast cancer

British Journal of Cancer (2022)

Alexios Matikas Athanasios Κotsakis Stella Apostolaki Helen Politaki Maria Perraki

Abstract Background The detection of circulating tumour cells (CTC) is prognostic for disease recurrence in early breast cancer (BC). This study aims to investigate whether this prognostic effect persists or varies over time. Methods The study population consisted of prospectively included stage I–III BC patients. The presence of CK19 mRNA-positive CTC in the peripheral blood was evaluated before and after adjuvant chemotherapy, using a real-time RT–PCR assay. Longitudinal samples were collected for a subset of patients. Results Baseline CTC data were available from 1220 patients, while 1132 had both pre- and post-therapy data. After a median follow-up of 134.1 months, CTC positivity at baseline was associated with shorter overall survival (OS; HR adj = 1.72, 95% CI 1.34–2.21, p < 0.001). For disease-free survival, an interaction with time ( p = 0.045) was observed. CTC positivity predicted early (within 5 years; HR adj = 1.76, 95 % CI 1.33–2.32, p < 0.001) but not late recurrence (HR adj = 1.10, 95% CI 0.79–1.53, p = 0.577). Following adjuvant chemotherapy, more patients converted from CTC-positive to CTC-negative than vice versa ( p < 0.001). Ten-year OS was 68.6% for + /+ and 86.7% for −/− group ( p < 0.001). CTC status at follow-up predicted disease recurrence. Conclusion CTC detection pre- and post-adjuvant chemotherapy is prognostic for early relapse, supporting investigations for novel adjuvant therapeutic approaches.

Adjuvant Chemotherapy

Circulating tumor cell

Adjuvant Therapy

10.1038/s41416-022-01699-5

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KRAS Genotypic Changes of Circulating Tumor Cells during Treatment of Patients with Metastatic Colorectal Cancer

PLoS ONE (2014)

Aristea Kalikaki Helen Politaki John Souglakos Stella Apostolaki E. Papadimitraki

Introduction Circulating tumor cells (CTCs) could represent a non-invasive source of cancer cells used for longitudinal monitoring of the tumoral mutation status throughout the course of the disease. The aims of the present study were to investigate the detection of KRAS mutations in CTCs from patients with metastatic colorectal cancer (mCRC) and to compare their mutation status during treatment or disease progression with that of the corresponding primary tumors. Materials and Methods Identification of the seven most common KRAS mutations on codons 12 and 13 was performed by Peptide Nucleic Acid (PNA)-based qPCR method. The sensitivity of the assay was determined after isolation of KRAS mutant cancer cells spiked into healthy donors' blood, using the CellSearch Epithelial Cell kit. Consistent detection of KRAS mutations was achieved in samples containing at least 10 tumor cells/7.5 ml of blood. Results The clinical utility of the assay was assessed in 48 blood samples drawn from 31 patients with mCRC. All patients had PIK3CA and BRAF wild type primary tumors and 14 KRAS mutant tumors. CTCs were detected in 65% of specimens obtained from 74% of patients. KRAS mutation analysis in CTC-enriched specimens showed that 45% and 16.7% of patients with mutant and wild type primary tumors, respectively, had detectable mutations in their CTCs. Assessing KRAS mutations in serial blood samples revealed that individual patient's CTCs exhibited different mutational status of KRAS during treatment. Conclusions The current findings support the rationale for using the CTCs as a dynamic source of tumor cells which, by re-evaluating their KRAS mutation status, could predict, perhaps more accurately, the response of mCRC patients to targeted therapy.

10.1371/journal.pone.0104902

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Comparison of Kras Mutation Status Between Primary Tumors and Circulating Tumor Cells in Patients with Metastatic Colorectal Cancer (MCRC)

Annals of Oncology (2013)

Aristea Kalikaki Helen Politaki Maria Tzardi E. Papadimitraki D. Mavroudis

Background: In metastatic colorectal cancer (mCRC), circulating tumor cell (CTC) analysis could represent a novel biopsy more representative of the current disease state and might be used as a biomarker of either sensitivity or acquired resistance to EGFR targeted therapy. The primary objective of this study was to investigate the feasibility of detecting KRAS mutations in CTC-enriched fractions isolated by the CellSearch system in patients with mCRC. Secondary objectives were to evaluate whether KRAS mutation status of CTCs correlates with that of corresponding primary tumors and examine the genetic heterogeneity of CTCs in respect to KRAS mutation status during treatment.Methods: Detection of the seven more common (codons 12 and 13) KRAS mutations was performed by the combination of the peptide nucleic acid (PNA) with allelic specific PCR in DNA isolated from the recovered cells following CTC enumeration using the CellSearch system. The technical feasibility to determine accurately the KRAS mutation status from a limited number of CTCs was validated by spiking tumor cells into healthy donors' blood. Consistent detection of KRAS mutations was achieved from samples containing an input of 20 cells.Results: A total of 48 blood samples were obtained from 17 patients with wild type and 14 with mutant KRAS primary tumors. All patients had primary tumors wild type for PIK3CA and BRAF. In 19 (61%) patients, blood samples were available from one time point and in 12 (39%) from at least 2 time points. Thirteen (42%) patients were chemotherapy-naïve at the time of first blood draw. Thirteen (27%) blood samples were collected prior to, 22 (46%) during the first-line chemotherapy, 10 (21%) at the time of disease progression on first-line treatment and 3 (6%) during the second-line chemotherapy. One or more CTCs were detected in 23 of 48 (48%) blood samples obtained from 15 of 31 (48%) patients; the average number of CTCs per 7.5 ml of blood was 96 (range 1-865). KRAS mutations were detected in 5 of the 13 (38%) CTC positive samples obtained from 3 of the 7 (43%) patients with KRAS mutant primary tumors and in 3 of the 10 (30%) CTC positive samples obtained from 2 of the 8 (25%) patients with KRAS wild type primary tumors. Analysis of serial blood samples revealed that the KRAS mutational status of CTCs may change during treatment and may be different from that of the corresponding primary tumors irrespective of treatment administration.Conclusion: These findings support the rationale for reassessing KRAS status on CTCs in order to predict more accurately, the response and evaluate the secondary resistance to anti-EGFR therapy of metastatic colorectal cancer patients. Background: In metastatic colorectal cancer (mCRC), circulating tumor cell (CTC) analysis could represent a novel biopsy more representative of the current disease state and might be used as a biomarker of either sensitivity or acquired resistance to EGFR targeted therapy. The primary objective of this study was to investigate the feasibility of detecting KRAS mutations in CTC-enriched fractions isolated by the CellSearch system in patients with mCRC. Secondary objectives were to evaluate whether KRAS mutation status of CTCs correlates with that of corresponding primary tumors and examine the genetic heterogeneity of CTCs in respect to KRAS mutation status during treatment. Methods: Detection of the seven more common (codons 12 and 13) KRAS mutations was performed by the combination of the peptide nucleic acid (PNA) with allelic specific PCR in DNA isolated from the recovered cells following CTC enumeration using the CellSearch system. The technical feasibility to determine accurately the KRAS mutation status from a limited number of CTCs was validated by spiking tumor cells into healthy donors' blood. Consistent detection of KRAS mutations was achieved from samples containing an input of 20 cells. Results: A total of 48 blood samples were obtained from 17 patients with wild type and 14 with mutant KRAS primary tumors. All patients had primary tumors wild type for PIK3CA and BRAF. In 19 (61%) patients, blood samples were available from one time point and in 12 (39%) from at least 2 time points. Thirteen (42%) patients were chemotherapy-naïve at the time of first blood draw. Thirteen (27%) blood samples were collected prior to, 22 (46%) during the first-line chemotherapy, 10 (21%) at the time of disease progression on first-line treatment and 3 (6%) during the second-line chemotherapy. One or more CTCs were detected in 23 of 48 (48%) blood samples obtained from 15 of 31 (48%) patients; the average number of CTCs per 7.5 ml of blood was 96 (range 1-865). KRAS mutations were detected in 5 of the 13 (38%) CTC positive samples obtained from 3 of the 7 (43%) patients with KRAS mutant primary tumors and in 3 of the 10 (30%) CTC positive samples obtained from 2 of the 8 (25%) patients with KRAS wild type primary tumors. Analysis of serial blood samples revealed that the KRAS mutational status of CTCs may change during treatment and may be different from that of the corresponding primary tumors irrespective of treatment administration. Conclusion: These findings support the rationale for reassessing KRAS status on CTCs in order to predict more accurately, the response and evaluate the secondary resistance to anti-EGFR therapy of metastatic colorectal cancer patients.

Circulating tumor cell

Liquid biopsy

Primary tumor

Cell-free fetal DNA

10.1093/annonc/mdt202.2

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