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Does primary neoadjuvant systemic therapy eradicate minimal residual disease? Analysis of disseminated and circulating tumor cells before and after therapy.

ABSTRACT: Patients with breast cancer (BC) undergoing neoadjuvant chemotherapy (NACT) may experience metastatic relapse despite achieving a pathologic complete response. We analyzed patients with BC before and after NACT for disseminated tumor cells (DTCs) in the bone marrow(BM); comprehensively characterized circulating tumor cells (CTCs), including stem cell-like CTCs (slCTCs), in blood to prove the effectiveness of treatment on these cells; and correlated these findings with response to therapy, progression-free survival (PFS), and overall survival (OS).CTCs (n?=?135) and slCTCs (n?=?91) before and after NACT were analyzed using the AdnaTest BreastCancer, AdnaTest TumorStemCell, and epithelial-mesenchymal transition (QIAGEN Hannover GmbH Germany). The expression of estrogen receptor, progesterone receptor, and the resistance marker excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1), nuclease were studied in separate single-plex reverse transcription polymerase chain reaction experiments. DTCs were evaluated in 142 patients before and 165 patients after NACT using the pan-cytokeratin antibody A45-B/B3 for immunocytochemistry.The positivity rates for DTCs, CTCs, and slCTCs were 27 %, 24 %, and 51 % before and 20 %, 8 %, and 20 % after NACT, respectively. Interestingly, 72 % of CTCs present after therapy were positive for ERCC1, and CTCs before (p?=?0.005) and after NACT (p?=?0.05) were significantly associated with the presence of slCTCs. Whereas no significant associations with clinical parameters were found for CTCs and slCTCs, DTCs were significantly associated with nodal status (p?=?0.03) and histology (0.046) before NACT and with the immunohistochemical subtype (p?=?0.02) after NACT. Univariable Cox regression analysis revealed that age (p?=?0.0065), tumor size before NACT (p?=?0.0473), nodal status after NACT (p?=?0.0137), and response to NACT (p?=?0.0136) were significantly correlated with PFS, whereas age (p?=?0.0162) and nodal status after NACT (p?=?0.0243) were significantly associated with OS. No significant correlations were found for DTCs or any CTCs before and after therapy with regard to PFS and OS.Although CTCs were eradicated more effectively than DTCs, CTCs detected after treatment seemed to be associated with tumor cells showing tumor stem cell characteristics as well as with resistant tumor cell populations that might indicate a worse outcome in the future. Thus, these patients might benefit from additional second-line treatment protocols including bisphosphonates for the eradication of DTCs.

SUBMITTER: Kasimir-Bauer S

PROVIDER: S-EPMC4751719 | biostudies-other | 2016 Feb

REPOSITORIES: biostudies-other

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Does primary neoadjuvant systemic therapy eradicate minimal residual disease? Analysis of disseminated and circulating tumor cells before and after therapy.

Kasimir-Bauer Sabine S Bittner Ann-Kathrin AK König Lisa L Reiter Katharina K Keller Thomas T Kimmig Rainer R Hoffmann Oliver O

Breast cancer research : BCR 20160212 1

<h4>Background</h4>Patients with breast cancer (BC) undergoing neoadjuvant chemotherapy (NACT) may experience metastatic relapse despite achieving a pathologic complete response. We analyzed patients with BC before and after NACT for disseminated tumor cells (DTCs) in the bone marrow(BM); comprehensively characterized circulating tumor cells (CTCs), including stem cell-like CTCs (slCTCs), in blood to prove the effectiveness of treatment on these cells; and correlated these findings with response ...[more]

PMID: 26868521

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Project description:The proliferative capacity of residual breast cancer (BC) disease indicates the existence of partial treatment resistance and higher probability of tumor recurrence. We explored the therapeutic potential of adding neoadjuvant metformin as an innovative strategy to decrease the proliferative potential of residual BC cells in patients failing to achieve pathological complete response (pCR) after pre-operative therapy. We performed a prospective analysis involving the intention-to-treat population of the (Metformin and Trastuzumab in Neoadjuvancy) METTEN study, a randomized multicenter phase II trial of women with primary, non-metastatic (human epidermal growth factor receptor 2) HER2-positive BC evaluating the efficacy, tolerability, and safety of oral metformin (850 mg twice-daily) for 24 weeks combined with anthracycline/taxane-based chemotherapy and trastuzumab (arm A) or equivalent regimen without metformin (arm B), before surgery. We centrally evaluated the proliferation marker Ki67 on sequential core biopsies using visual assessment (VA) and an (Food and Drug Administration) FDA-cleared automated digital image analysis (ADIA) algorithm. ADIA-based pre-operative values of high Ki67 (≥20%), but not those from VA, significantly predicted the occurrence of pCR in both arms irrespective of the hormone receptor status (p = 0.024 and 0.120, respectively). Changes in Ki67 in residual tumors of non-pCR patients were significantly higher in the metformin-containing arm (p = 0.025), with half of all patients exhibiting high Ki67 at baseline moving into the low-Ki67 (<20%) category after neoadjuvant treatment. By contrast, no statistically significant changes in Ki67 occurred in residual tumors of the control treatment arm (p = 0.293). There is an urgent need for innovative therapeutic strategies aiming to provide the protective effects of decreasing Ki67 after neoadjuvant treatment even if pCR is not achieved. Metformin would be evaluated as a safe candidate to decrease the aggressiveness of residual disease after neoadjuvant (pre-operative) systemic therapy of BC patients.

Project description:Engineered autologous acute myeloid leukemia (AML) cells present multiple leukemia-associated and patient-specific antigens and as such hold promise as immunotherapeutic vaccines. However, prior vaccines have not reliably induced effective antileukemic immunity, in part because AML blasts have immune inhibitory effects and lack expression of the critical costimulatory molecule CD80. To enhance induction of leukemia-specific cytolytic activity, 32Dp210 murine AML cells were engineered to express either CD80 alone, or the immunostimulatory cytokine interleukin-15 (IL-15) with its receptor ? (IL-15R?), or heterodimeric IL-15/IL-15R? together with CD80 and tested as irradiated cell vaccines. IL-15 is a ?c-chain cytokine, with unique properties suited to stimulating antitumor immunity, including stimulation of both natural killer and CD8+ memory T cells. Coexpression of IL-15 and IL-15R? markedly increases IL-15 stability and secretion. Non-tumor-bearing mice vaccinated with irradiated 32Dp210-IL-15/IL-15R?/CD80 and challenged with 32Dp210 leukemia had greater survival than did mice treated with 32Dp210-CD80 or 32Dp210-IL-15/IL-15R? vaccines, whereas no unvaccinated mice inoculated with leukemia survived. In mice with established leukemia, treatment with 32Dp210-IL-15/IL-15R?/CD80 vaccination stimulated unprecedented antileukemic immunity enabling 80% survival, an effect that was abrogated by anti-CD8 antibody-mediated depletion in vivo. Because, clinically, AML vaccines are administered as postremission therapy, we established a novel model in which mice with high leukemic burdens were treated with cytotoxic therapy to induce remission (<5% marrow blasts). Postremission vaccination with 32Dp210-IL-15/IL-15R?/CD80 achieved 50% overall survival in these mice, whereas all unvaccinated mice achieving remission subsequently relapsed. These studies demonstrate that combined expression of IL-15/IL-15R? and CD80 by syngeneic AML vaccines stimulates effective and long-lasting antileukemic immunity.

Project description:BackgroundBreast cancer mortality is principally due to tumor recurrence, which can occur following extended periods of clinical remission that may last decades. While clinical latency has been postulated to reflect the ability of residual tumor cells to persist in a dormant state, this hypothesis remains unproven since little is known about the biology of these cells. Consequently, defining the properties of residual tumor cells is an essential goal with important clinical implications for preventing recurrence and improving cancer outcomes.MethodsTo identify conserved features of residual tumor cells, we modeled minimal residual disease using inducible transgenic mouse models for HER2/neu and Wnt1-driven tumorigenesis that recapitulate cardinal features of human breast cancer progression, as well as human breast cancer cell xenografts subjected to targeted therapy. Fluorescence-activated cell sorting was used to isolate tumor cells from primary tumors, residual lesions following oncogene blockade, and recurrent tumors to analyze gene expression signatures and evaluate tumor-initiating cell properties.ResultsWe demonstrate that residual tumor cells surviving oncogenic pathway inhibition at both local and distant sites exist in a state of cellular dormancy, despite adequate vascularization and the absence of adaptive immunity, and retain the ability to re-enter the cell cycle and give rise to recurrent tumors after extended latency periods. Compared to primary or recurrent tumor cells, dormant residual tumor cells possess unique features that are conserved across mouse models for human breast cancer driven by different oncogenes, and express a gene signature that is strongly associated with recurrence-free survival in breast cancer patients and similar to that of tumor cells in which dormancy is induced by the microenvironment. Although residual tumor cells in both the HER2/neu and Wnt1 models are enriched for phenotypic features associated with tumor-initiating cells, limiting dilution experiments revealed that residual tumor cells are not enriched for cells capable of giving rise to primary tumors, but are enriched for cells capable of giving rise to recurrent tumors, suggesting that tumor-initiating populations underlying primary tumorigenesis may be distinct from those that give rise to recurrence following therapy.ConclusionsResidual cancer cells surviving targeted therapy reside in a well-vascularized, desmoplastic microenvironment at both local and distant sites. These cells exist in a state of cellular dormancy that bears little resemblance to primary or recurrent tumor cells, but shares similarities with cells in which dormancy is induced by microenvironmental cues. Our observations suggest that dormancy may be a conserved response to targeted therapy independent of the oncogenic pathway inhibited or properties of the primary tumor, that the mechanisms underlying dormancy at local and distant sites may be related, and that the dormant state represents a potential therapeutic target for preventing cancer recurrence.

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Does primary neoadjuvant systemic therapy eradicate minimal residual disease? Analysis of disseminated and circulating tumor cells before and after therapy.

Publications

Does primary neoadjuvant systemic therapy eradicate minimal residual disease? Analysis of disseminated and circulating tumor cells before and after therapy.

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