Early metabolic response to neoadjuvant letrozole, measured by FDG PET/CT, is correlated with a decrease in the Ki67 labeling index in patients with hormone receptor-positive primary breast cancer: A pilot study

Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.
Breast Cancer (Impact Factor: 1.59). 10/2011; 18(4):299-308. DOI: 10.1007/s12282-010-0212-y
Source: PubMed


To assess whether the early metabolic response evaluated by (18)F-fluorodeoxy-glucose positron emission combined with computed tomography (FDG PET/CT) predicts the morphological, pathological, and cell-cycle responses to neoadjuvant endocrine therapy of hormone receptor-positive primary breast cancer.
Eleven patients (12 tumors) with estrogen receptor-positive (Allred score 7 or 8) primary breast cancer were enrolled. All patients received a daily dose (2.5 mg) of letrozole for 12 weeks followed by surgery. Sequential FDG PET/CT scans were performed before treatment (baseline), at 4 weeks after the initiation of endocrine therapy (PET2), and prior to surgery (PET3). Tumors showing a 40% or more reduction and those showing a less than 40% reduction in the standardized uptake value maximum (SUV(max)) at PET2 compared with the baseline PET were defined as metabolic responders and metabolic nonresponders, respectively. Change in tumor size as measured by ultrasound (morphological response), pathological response, and change in the Ki67 labeling index in tumor tissue (cell-cycle response) during the neoadjuvant letrozole therapy were compared between the metabolic responders and nonresponders.
The average decreases in SUV(max) at PET2 compared with the baseline PET in the metabolic responders (n = 6) and the metabolic nonresponders (n = 6) were 60.9% (±21.3 SD) and 14.2% (±12.0 SD), respectively. At PET3 compared with the baseline PET, the metabolic responders showed a significantly higher decrease of 64.5% (±18.7 SD) (p = 0.0004), whereas the nonresponders showed a nonsignificant decrease of 16.7% (±14.1 SD) (p = 0.06). The morphological and pathological responses after letrozole therapy did not differ between the metabolic responders and nonresponders. The metabolic responders showed a marked decrease in the Ki67 labeling index at 2 weeks after the initiation of treatment (62.9%, ±35.9 SD, p = 0.04) and at surgery (91.7%, ±10.7 SD, p = 0.03) compared with the baseline values. In contrast, metabolic nonresponders showed no significant change in the Ki67 index either after 2 weeks of therapy or at surgery.
Cell-cycle response monitored by the Ki67 labeling index correlates with metabolic response monitored by tumor SUV(max). Monitoring of tumor SUV(max) using FDG PET/CT may be feasible to predict cell-cycle response to neoadjuvant endocrine therapy of primary breast cancer.

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    • "Other diagnostic techniques such as FDG-PET, which measures the uptake of labeled glucose into a tumor, are thus better suited to evaluate biological activity at a given point in time and are currently evaluated [26], [27]. An alternative to evaluate the presence of viable tumor cells is by measuring the readily available immunohistochemical analysis of the nuclear antigen Ki67 [28]. There is now increasing interest in the nuclear proliferation antigen Ki67, since allows to distinguish the relatively chemo-resistant luminal A from the more sensitive luminal B breast cancer subtype [29]. "
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    ABSTRACT: Although the use of (neo-)adjuvant chemotherapy in breast cancer patients has resulted in improved outcome, not all patients benefit equally. We have evaluated the utility of an in vitro chemosensitivity assay in predicting response to neoadjuvant chemotherapy. Pre-therapeutic biopsies were obtained from 30 breast cancer patients assigned to neoadjuvant epirubicin 75 mg/m2 and docetaxel 75 mg/m2 (Epi/Doc) in a prospectively randomized clinical trial. Biopsies were subjected to a standardized ATP-based Epi/Doc chemosensitivity assay, and to gene expression profiling. Patients then received 3 cycles of chemotherapy, and response was evaluated by changes in tumor diameter and Ki67 expression. The efficacy of Epi/Doc in vitro was correlated with differential changes in tumor cell proliferation in response to Epi/Doc in vivo (p = 0.0011; r = 0.73670, Spearmańs rho), but did not predict for changes in tumor size. While a pre-therapeutic gene expression signature identified tumors with a clinical response to Epi/Doc, no such signature could be found for tumors that responded to Epi/Doc in vitro, or tumors in which Epi/Doc exerted an antiproliferative effect in vivo. This is the first prospective clinical trial to demonstrate the utility of a standardized in vitro chemosensitivity assay in predicting the individual biological response to chemotherapy in breast cancer.
    PLoS ONE 06/2013; 8(6):e66573. DOI:10.1371/journal.pone.0066573 · 3.23 Impact Factor
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    • "In order to gain insights into mechanisms by which LOX-PP inhibits tumor growth in vivo, we first evaluated relative expression levels of Ki-67 by immunohistochemistry in harvested tumors. Ki-67 is a marker for cell proliferation, and is expressed in all phases of the cell cycle except G0, and is a predictive and prognostic marker for breast cancer [27], [28], [29], [30], [31]. A higher number of Ki-67 immunopositive cells were observed in sections injected with PBS or implanted with empty beads compared to rLOX-PP injection or rLOX-PP/alginate beads implantation, as seen in representative sections (Figure 4A and 4B). "
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    ABSTRACT: Lysyl oxidase propeptide (LOX-PP) ectopic overexpression inhibits the growth of cancer xenografts. Here the ability and mode of action of purified recombinant LOX-PP (rLOX-PP) protein to inhibit the growth of pre-existing xenografts was determined. Experimental approaches employed were direct intratumoral injection (i.t.) of rLOX-PP protein into murine breast cancer NF639 xenografts, and application of a slow release formulation of rLOX-PP implanted adjacent to tumors in NCR nu/nu mice (n = 10). Tumors were monitored for growth, and after sacrifice were subjected to immunohistochemical and Western blot analyses for several markers of proliferation, apoptosis, and for rLOX-PP itself. Direct i.t. injection of rLOX-PP significantly reduced tumor volume on days 20, 22 and 25 and tumor weight at harvest on day 25 by 30% compared to control. Implantation of beads preloaded with 35 micrograms rLOX-PP (n = 10) in vivo reduced tumor volume and weight at sacrifice when compared to empty beads (p<0.05). A 30% reduction of tumor volume on days 22 and 25 (p<0.05) and final tumor weight on day 25 (p<0.05) were observed with a reduced tumor growth rate of 60% after implantation. rLOX-PP significantly reduced the expression of proliferation markers and Erk1/2 MAP kinase activation, while prominent increases in apoptosis markers were observed. rLOX-PP was detected by immunohistochemistry in harvested rLOX-PP tumors, but not in controls. Data provide pre-clinical findings that support proof of principle for the therapeutic anti-cancer potential of rLOX-PP protein formulations.
    PLoS ONE 02/2012; 7(2):e31188. DOI:10.1371/journal.pone.0031188 · 3.23 Impact Factor

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