Influence of denosumab on disseminated tumor cells (DTC) in the bone marrow of breast cancer (BC) patients with neoadjuvant treatment: A GeparX translational substudy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 580-580
Author(s):  
Pauline Wimberger ◽  
Jens U. Blohmer ◽  
Petra Krabisch ◽  
Theresa Link ◽  
Marianne Just ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Neoadjuvant Chemotherapy ◽  
Tumor Cells ◽  
Neoadjuvant Treatment ◽  
Complete Response ◽  
Disseminated Tumor Cells ◽  
Primary Diagnosis ◽  
Phase Iii ◽  
Specific Analysis ◽  
First Time

580 Background: DTCs in the bone marrow are observed in up to 30% at primary diagnosis of BC and their presence is an independent prognostic factor for reduced survival. It was shown that antiresorptive therapy eradicates DTCs and improves prognosis in DTC-positive BC patients (pts). In the GeparX phase III prospective randomized trial, denosumab (a monoclonal IgG2-anti-RANKL-antibody) was investigated as add-on treatment to neoadjuvant chemotherapy (NACT) with two different nab-paclitaxel schedules in early high-risk primary BC. In a translational substudy, we analyzed for the first time the influence of short-term denosumab treatment (24 weeks) on the presence of DTCs. Methods: A total of 167 pts from the GeparX trial were analyzed for DTCs at baseline by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. Initially DTC-positive pts were re-analyzed for DTCs after NACT±Denosumab. Results: Overall, 60/167 pts (35.9%) treated with NACT±Denosumab had a pathological complete response (pCR; 55.4% in TNBC, 43.3% in HER2+, 15.3% in HR+/HER2-). At baseline, 43/167 pts (25.7%) were DTC-positive and 41 of those were available for re-analysis of DTCs after NACT±Denosumab. DTC eradication was observed in 77.8% after NACT+Denosumab and in 69.6% after NACT alone (p = 0.726). Due to the limited number of pts eligible for DTC-re-analysis after NACT, a subtype specific analysis for the effect of denosumab was not possible. There was no significant association between pCR and i) the presence of DTCs at baseline (37.1% DTC-negative vs 32.6% positive, p = 0.71) or ii) the eradication of DTCs after NACT±Denosumab (36.7% vs 27.3%, p = 0.72). Notably, in TNBC, we observed a tendency that DTC-positivity at baseline or DTC-persistence after NACT could be associated with reduced pCR rate (40.0% in DTC-positive vs. 66.7% in DTC-negative pts, p = 0.16; 25% in DTC-persistent pts vs. 50% in DTC-eradicated pts, p = 0.59). Conclusions: Denosumab in addition to NACT does not improve pCR, but the suspected effect of denosumab on DTC eradication should be further analyzed in TNBC. Key words: GeparX trial, denosumab, disseminated tumor cells, bone marrow, neoadjuvant chemotherapy. Funding: GeparX and DTC substudy were financially supported by Amgen and Celgene. Clinical trial information: NCT02682693 .

Disseminated tumor cells in primary breast cancer: Evaluation of the percentage of breast cancer stem cells in bone marrow aspirates of patients receiving neoadjuvant chemotherapy

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 505-505 ◽  
Author(s):  
J. M. Reuben ◽  
B. Lee ◽  
A. Lucci ◽  
H. Gao ◽  
E. N. Cohen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Bone Marrow ◽  
Neoadjuvant Chemotherapy ◽  
Tumor Cells ◽  
Primary Breast Cancer ◽  
Disseminated Tumor Cells ◽  
Notch 1 ◽  
Spearman's Rho ◽  
Her 2

505 Background: Disseminated tumor cells (DTC) in the bone marrow (BM) are related to poor prognosis of primary breast cancer (PBC). Cancer-initiating stem cells (CSC) have been detected in BM of PBC patients. Downregulation of the Notch pathway leads to murine mammary stem cell expansion and its expression is an early event in breast cancer. We enumerated CSC in BM mononuclear cells (BMC) and assessed the expression of Notch-1, ER, and HER-2 to study the differences between untreated patients and those treated with neoadjuvant chemotherapy. Methods: BM was collected from 90 PBC patients at time of surgery to assess DTC (CD326+CD45-) and CSC (CD326+CD45-CD44+CD24-) by FACS analysis. BM samples were also interrogated for the presence of CSC with ALDH activity using the Aldefluor® detection kit. RNA extracted from 61 BMC was analyzed for Notch-1, ER, and HER-2 transcripts by RT-PCR; the level of each transcript was normalized to that of the housekeeping gene, GAPDH. Results: The median age of patients is 51 years old (range, 27–77 years). A total of 29 patients (32%) received neoadjuvant chemotherapy, including 8 patients with anti-HER-2 targeted therapy. BMC of neoadjuvant-treated patients had a significantly higher median percentage of CSC in BMC (P= 0.046) and a significantly higher proportion of CSC cells within the Aldefluor+ population (P= 0.013) than those of untreated patients. Median level of Notch-1 transcripts in BMC was lower in neoadjuvant-treated patients compared with that of untreated patients (P= 0.07). There was an inverse correlation between the level of Notch-1 transcripts and the percentage of CSC in BMC of untreated (Spearman's rho= -0.519, P < 0.001), but not in neoadjuvant treated (Spearman's rho= -0.483, P= 0.058) patients. Conclusions: Neoadjuvant chemotherapy is associated with expansion of CSC in the BMC of patients with PBC. Untreated patients with higher level of Notch-1 transcripts in the BMC tend to have lower percentages of CSC and suggest that Notch signaling may be crucial for differentiation of CSC. The prognostic value of this finding is under investigation and gene expression profile of CSC may provide indications for novel neoadjuvant therapies. No significant financial relationships to disclose.

INNOVA: Interval or neoadjuvant chemotherapy in rectal cancer—A phase II randomized study comparing interval versus neoadjuvant chemotherapy in magnetic resonance imaging-defined high-risk rectal cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 91-91
Author(s):  
Ramakrishnan Ayloor Seshadri ◽  
Trivadi S. Ganesan ◽  
Manikandan Dhanushkodi ◽  
Arunkumar M N ◽  
Shirley Sundersingh
Keyword(s):  
Clinical Trial ◽  
Rectal Cancer ◽  
High Risk ◽  
Neoadjuvant Chemotherapy ◽  
Randomized Study ◽  
Neoadjuvant Treatment ◽  
Complete Response ◽  
Phase Iii ◽  
Clinical Trial Registry ◽  
Grade 3

91 Background: Total neoadjuvant treatment is a promising option in rectal cancer. We aim to compare neoadjuvant versus interval chemotherapy in high risk rectal cancer to identify the optimal sequencing of treatment. Methods: Using a Simon two-stage design, newly diagnosed MRI defined high risk rectal cancer patients were randomly assigned in a 1:1 ratio to receive three 21 day cycles of chemotherapy with Capecitabine 1000 mg/m2 and Oxaliplatin 130 mg/m2 either before (Arm A-neoadjuvant) or after (Arm B-interval) chemoradiation followed by surgery. Primary end point was the pathological complete response (pCR) following surgery. A heirarchial model was used to assess the primary and secondary end points (toxicity and compliance) and compare the two regimens. (Clinical Trial Registry of India No. CTRI/2015/01/005385). Results: In this single centre study conducted between November 2015 and February 2020, 42 patients were randomised in the first stage. A pCR was seen in 4 patients in Arm A and 6 in Arm B. Hence another 52 patients were randomised in the second stage of which an additional 3 and 2 patients had a pCR leading to an overall pCR of 7 and 8 patients (15.5% vs 17% and 18.4% vs 19.5% in the intent-to-treat and per-protocol populations in Arm A and B respectively. This exceeded the minimum predetermined number of 5 pCR needed to qualify for further evaluation for each arm. Grade ≥3 toxicity was observed in 2.2% of 132 cycles and 4.6% of 129 cycles of chemotherapy delivered in 45 and 43 patients in Arm A and B respectively while 11/43 (25.5%) and 10/47 (21.2%) patients experienced grade ≥3 toxicity during chemoradiation. Treatment break of > 7 days was seen in 23.2% and 29.7% of patients in Arm A and B respectively while 93.3% in Arm A and 100% of patients in Arm B completed all 3 planned cycles of pre-operative chemotherapy. A non-significant trend towards greater pathological downstaging was seen in Arm B than in Arm A (ypT1-2 39% vs 26.3%; p = 0.1 and ypN0 68.3% vs 57.9%; p = 0.5 respectively). Conclusions: In this phase two study, both neoadjuvant and interval chemotherapy emerged eligible for further evaluation against the standard of care in a future phase III study. Although we could not pick one winner based on pCR, toxicity or compliance, the greater downstaging observed with interval chemotherapy suggests it could play a greater role in an organ preservation approach. Clinical trial information:CTRI/2015/01/005385, UTN no: U111111650578.

Apoptotic disseminated tumor cells reflect response to primary chemotherapy in breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 654-654
Author(s):  
T. N. Fehm ◽  
S. Becker ◽  
D. Wallwiener ◽  
G. Gebauer ◽  
E. Solomayer
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Therapy Response ◽  
Complete Response ◽  
Disseminated Tumor Cells ◽  
Primary Chemotherapy ◽  
Breast Cancer Patients ◽  
Primary Systemic Therapy

654 Background: Primary chemotherapy (pCHT) is an established method to reduce tumor size (downstaging) in breast cancer patients before performing breast conserving therapy. The consequences of pCHT on tumor cell dissemination in these patients are not known. The aim of this study was to investigate (1) the incidence of disseminated tumor cells (DTC) including apoptotic DTC in patients with breast cancer after primary chemotherapy and (2) its correlation with pathological therapy response. Methods: Bone marrow aspiration was performed in 157 patients after primary chemotherapy. Cytokeratin-positive cells were detected by immunocytochemistry using the AB45-B/B3 anti-cytokeratin antibody. For detection of apoptotic tumor cells the antibody M30 (Roche Diagnostics, Germany) was used. M30 reacts with a neo-epitope expressed only after caspase cleavage of CK 18 during early apoptosis. Results: The incidence of disseminated tumor cells in breast cancer patients was 57% (84 of 157 pts) after completion of primary systemic therapy. Tumor dissemination was observed more frequently in patients with no change/progressive disease (NC+PD: 63%) than in those who showed partial (PR) or complete remission (CR) of the primary tumor (PR+CR: 43%) (p<0.05). However, 9 of 23 (40%) patients with complete response were still bone marrow positive. Apoptotic tumor cells were present in 36 of 157 (23%) breast cancer patients. The positivity rate of apoptotic cells was higher in bone marrow positive patients with PR or CR (42%) compared to those with stable disease (SD) (26%). No apoptotic tumor cells were detected in patients with tumor progression (n=5). Conclusions: The pathological therapy response is reflected by the presence of apoptotic tumor cells in the bone marrow of breast cancer patients. However, patients with complete response may still have non apoptotic disseminated tumor cells. Patients with tumor cell dissemination after primary systemic therapy may be benefit from additional secondary adjuvant treatment (e.g. bisphosphonates, antibody based strategies). No significant financial relationships to disclose.

Disseminated tumor cells in bone marrow of breast cancer patients–Comparison of immunocytochemistry and RT-PCR

2006 ◽  
Vol 66 (S 01) ◽  
Author(s):  
T Fehm ◽  
S Becker ◽  
MJ Banys ◽  
G Becker-Pergola ◽  
S Duerr-Stoerzer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Disseminated Tumor Cells ◽  
Breast Cancer Patients ◽  
Rt Pcr

Perioperative Activation of Disseminated Tumor Cells in Bone Marrow of Patients With Prostate Cancer

2009 ◽  
Vol 27 (10) ◽  
pp. 1549-1556 ◽  
Author(s):  
Dorothea Weckermann ◽  
Bernhard Polzer ◽  
Thomas Ragg ◽  
Andreas Blana ◽  
Günter Schlimok ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Marrow ◽  
Tumor Cells ◽  
Cox Regression ◽  
Systemic Disease ◽  
Disseminated Tumor Cells ◽  
Comparative Genomic ◽  
Prognostic Impact ◽  
Primary Tumors ◽  
Cox Regression Analysis

Purpose The outcome of prostate cancer is highly unpredictable. To assess the dynamics of systemic disease and to identify patients at high risk for early relapse we followed the fate of disseminated tumor cells in bone marrow for up to 10 years and genetically analyzed such cells isolated at various stages of disease. Patients and Methods Nine hundred bone marrow aspirates from 384 patients were stained using the monoclonal antibody A45-B/B3 directed against cytokeratins 8, 18, and 19. Log-rank statistics and Cox regression analysis were applied to determine the prognostic impact of positive cells detected before surgery (244 patients) and postoperatively (214 patients). Samples from primary tumors (n = 55) and single disseminated tumor cells (n = 100) were analyzed by comparative genomic hybridization. Results Detection of cytokeratin-positive cells before surgery was the strongest independent risk factor for metastasis within 48 months (P < .001; relative risk [RR], 5.5; 95% CI, 2.4 to 12.9). In contrast, cytokeratin-positive cells detected 6 months to 10 years after radical prostatectomy were consistently present in bone marrow with a prevalence of approximately 20% but had no influence on disease outcome. Characteristic genotypes of cytokeratin-positive cells were selected at manifestation of metastasis. Conclusion Cytokeratin-positive cells in the bone marrow of prostate cancer patients are only prognostically relevant when detected before surgery. Because we could not identify significant genetic differences between pre- and postoperatively isolated tumor cells before manifestation of metastasis, we postulate the existence of perioperative stimuli that activate disseminated tumor cells. Patients with cytokeratin-positive cells in bone marrow before surgery may therefore benefit from adjuvant therapies.

901 Single disseminated tumor cells in bone marrow and PBSC in patients with small cell lung cancer

Lung Cancer ◽  
1997 ◽  
Vol 18 ◽  
pp. 229-230
Author(s):  
U. Seifart ◽  
S. Henrich ◽  
G. Jaques ◽  
C. Loechelt ◽  
A. Wachtel ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Bone Marrow ◽  
Small Cell Lung Cancer ◽  
Tumor Cells ◽  
Cell Lung Cancer ◽  
Disseminated Tumor Cells ◽  
Small Cell ◽  
Small Cell Lung
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