Abstract P2-05-08: Combined neoadjuvant iniparib and carboplatin in locally advanced or metastatic canine mammary tumors (MT) to support human clinical studies
F. MorioSonia BecavinAnne GognyFrédérique NguyenOlivier AlbaricSophie LabrutCéline SévenoPatricia VrignaudPhilippe JuinMario CamponeJérôme AbadieCatherine Ibisch
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Abstract INTRODUCTION Among breast cancers, the triple negative subtype (negative for hormone receptors and not overexpressing HER2) has the worst prognosis and its response to Iniparib has been investigated in clinical trials. Further investigations are needed to optimize drug schedule and patient selection criteria. Iniparib antitumor mechanism is not completely understood, as well as iniparib diffusion kinetic into tumoral tissues. We address these questions in spontaneous canine invasive mammary carcinomas, which are a good model for this cancer subtype (Ibisch et al., World Veterinary Cancer Congress 2012), in a neoadjuvant setting. To our knowledge, this is the first study of iniparib administration in cancer-bearing dogs. MATERIAL AND METHODS Twenty female dogs with spontaneous MT with malignant criteria (tumor size, speed of growth, ulceration, relapse, or metastasis) were included. All tumors were described as rapidly growing. Dogs received a first infusion of iniparib at day 0 and a combination of carboplatin and iniparib at day 7. Biological materials (tumor biopsies and blood) were collected before and 5 minutes after iniparib infusion for pharmacokinetic and metabolism studies. Tumor response was evaluated by caliper measurements and histopathological analysis of mammary tumors and draining lymph nodes. A chain mastectomy was performed 3 or 4 weeks later. Histological records included the subtype of carcinoma (WHO 1999), Elston & Ellis grade, presence of emboli, lymph node metastasis and IHC stainings using ER, PR, Her2 (scored according to Wolff et al.2007), CK5/6, EGF-R and Ki67. Intensity of necrosis and apoptosis was evaluated using PAS coloration and immunohistochemistry for caspase 3, at DO on tumor biopsies and at surgery. Toxicity of the protocol was evaluated and its efficiency on invasive carcinomas was compared to surgery alone (control group of 27 female dogs with invasive mammary carcinomas treated by chain mastectomy alone). RESULTS Treated and control groups shared similar features concerning animal breeds, age, neutering status and tumor location. 75% of the treated MT were malignant. Necrosis and apoptosis were significantly increased in respectively 63 and 56% of iniparib treated tumors. Clinical evidence of toxicity was minimal (15% of dogs with nausea, 60% with transient polyuria-polydipsia). Tumor stabilization was observed before surgery in all dogs but one. Median survival has not been reached. CONCLUSION Iniparib at 35mg/kg combined with carboplatin at 300 mg/m2 seemed well tolerated in this study and deserves further investigations. The degree of necrosis and apoptosis in the treated tumors can be evaluated with these techniques. Iniparib pharmacokinetic and metabolism studies in cancer-bearing dogs are ongoing. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-05-08.Keywords:
Carboplatin
Axillary lymph nodes
Axilla
Mammary tumor
Objective To determine the effect of postoperative adjuvant radiation therapy for breast cancer patients with T 1～3 and eight or more positive axillary lymph nodes. Methods Seventy eight patients treated between 1983 and 1991 in Cancer Hospital of Chinese Academy of Medical Science were retrospectively analyzed, All patients, with histologically confirmed invasive carcinomas of the breast, received half to four courses of adjuvant chemotherapy after radical surgery. Radiation therapy to the ipsilateral supraclavicular, infraclavicular and internal mammary nodes with or without chest wall and axillary nodes was given to 38 patients, the majority were treated to a dose of more than 45 Gy. Results For the radiation group and no radiation group, the five year initial locoregional recurrence rates were 30.8% and 57.4% (P=0.010), the disease free survival rates were 47.7% and 15.7%(P=0.002), the overall survival rates were 64.4% and 40.6%(P=0.083), respectively. The crude chest wall recurrence rate was 7.7% (2/26) for the patients who received chest wall irradiation as compared with 3/9 for the patients who did not receive chest wall irradiation. The crude axilla recurrence rate was 4.0% (1/25) for the patients who received axilla irradiation as compared with 7.7% (1/13) for the patients who did not received axilla irradiation. Conclusions Besides adjuvant chemotherapy, radiation therapy should be routinely given to the breast cancer patients with T 1～3 and eight or more positive axillary lymph nodes. In radiation therapy, chest wall should be one of the routine irradiated sites, axillary irradiation is not necessary.
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Background: The recommended surgical procedure for the involved lymph nodes (LNs) in breast cancer is axillary nodes dissection (AND), even after pathological complete response (PCR) to neo-adjuvant chemotherapy (NACT). Many trials are studying the benefit of re-staging the axilla post NACT with targeted nodes dissection (TAD) with the assumption that they can represent the whole axillary response, and if they show PCR then those patients can avoid the potentially morbid AND. The TAD technique is showing promising results but still there are significant false negative rates (FNR). In this study our aim is to identify common imaging and/or histopathology characteristics in patients who showed PCR in the axilla. This subgroup if found with predictable axillary PCR can be a target for TAD in future studies with possibly less FNR. Methods: Retrospective data collected from all patients with axillary metastasis underwent NACT in our institution between 2009 and 2017. Pre and post-surgery imaging and final histopathology characteristics were compared to the axillary response to NACT. Analysis done using R. Citation: R Core Team (in 2018). Results: We found statistically significant association between PCR in the axilla and HER2+ cancers (P=0.012), absent lympho-vascular invasion (LVI) (P<0.001), and complete main tumour response to NACT (P<0.001). Relation of axillary response to ER, PR, and MRI were statistically insignificant (P=0.120, 0.249, and 0.310). Conclusions: It is possible to find a subgroup with predictable PCR showing common characteristics like LVI negative, HER2 positive, and main tumour PCR. Findings can help in further prospective studies.
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Axillary ultrasound (US) is often part of the routine assessment of the clinically negative axilla in primary breast cancer, which determines the extent of axillary surgery to be performed. This study aims to ascertain the burden of disease in the axilla of patients with a normal clinical examination (cN0) but with US detected metastatic axillary lymph nodes.
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Metastatic involvement of the axillary lymph nodes is the most important prognostic factor in breast cancer. Preoperative knowledge of lymph node status would be useful in planning the therapy for breast cancer. The aim of our study was to find how accurately metastatic lymph nodes can be detected with ultrasonography (US). Our study consisted of 63 breast cancer patients having 65 breast cancers. Their axillae were examined preoperatively with US (with a 7.5 Mhz linear-array transducer). 27.7% of these patients had metastatic axillary lymph nodes. With US we could detect 12 of these 18 axillary metastases. In 2 of our 6 false negative results only micrometastases were found on histological examination. In our study the sensitivity of US was 66.6%. There was only one axilla, in which nodes were detected with US, but on histological examination no metastases were found, thus giving a specificity of 97.9%. Our study indicates that in the axilla normal nodes are not visible with US.
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All breast cancer patients are examined to check for the presence of malignant tumour cells that may have spread to the axillary lymph nodes. Following an ultrasound of the axilla, one or more lymph nodes are surgically removed for this purpose. This dissertation shows, among other things, that a contrast-enhanced MRI scan of the axilla could provide a promising alternative to surgical removal of the lymph nodes. If the validation study confirms this, surgery could be avoided in 70% of new breast cancer patients, because they do not have metastases in the lymph nodes. They would also be less exposed to the potential effects of axillary surgery, such as problems with shoulder movement, arm swelling due to a build-up of lymph fluid, or changes in arm sensitivity.
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To study the effect of Runing II (a Chinese herbal preparation for mammary cancer) on the growth and metastasis of transplanted tumor of mammary cancer MA-891-bearing TA2 mice and its mechanism. The model of mammary cancer MA-891 cell strain transplanted tumor of TA2 mice with lung metastasis were developed to observe the effect of Runing II on the growth and metastasis of the transplanted tumor. The immunohistochemical method and image analysis were adopted to detect the levels of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), and micro-vessel count (MVC) and micro-vessel area (MVA). In the Runing II group, the tumor weight inhibition rate and the lung metastasis inhibition rate were 37.3% and 65.4% respectively, the tumor growth and lung metastasis were obviously inhibited; And the levels of VEGF and VEGFR, MVC and MVA were significantly decreased as compared with those in the tumor-bearing control group (P<0.05). The Chinese herbal preparation Running II can inhibit the metastasis of tumor through inhibiting the angiogenesis, and the mechanism is possibly related with down-regulation of VEGF and VEGFR expression.
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