The gut microbiome has been shown to influence the response of tumors to anti–PD-1 (programmed cell death–1) immunotherapy in preclinical mouse models and observational patient cohorts. However, modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti–PD-1 immunotherapy in 10 patients with anti–PD-1–refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.

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Background: Her-2-neu is one of the major genes and proteins, whose amplification and expression is widely used in modern medical practice in patients with breast carcinoma (BC). . This is a marker of poor prognosis and the "target" for Herceptin. The role of this marker in brain metastases is not very well investigated as it is in a primary tumor. Aim: To investigate the incidence of molecular variants of breast carcinoma in brain metastases (BM), to analyze Her-2-neu presence in them and evaluate its prognostic significance in patients with BMBC. Patients and methods: 90 FFPE tumor tissues and clinical data from consented patients with BMBC treated with surgery at the NN Burdenko Neurosurgery Institute (median age 52, age range 29-73 years) and 71 FFPE tumor tissues and clinical data from consented patients with primary BC without BM treated with surgery in AI Burnacyan Institute (median age 58, age range 28-80 years) have been obtained and evaluated. IHC staining of all 161 cases was performed with monoclonal antibodies to ER, PR, Ki-67and Her-2-neu (DAKO); Fluorescence in situ hybridization Her-2-neu LSI and CEP17 was also performed . Her-2 neu expression and amplification were estimated according to the standard ASCO recommendations. A special questionnaire was completed in order to obtain information about outcome of the patients. Statistical analysis was performed using the STATISTICA 8.0 software. Results: There were 5 molecular variants in BC and BMBC groups according to the ER, PR, Ki-67 and Her-2-Neu IHC expression and Her-2-Neu amplification. Their incidence among two groups were: luminal A - 42% vs. 9%, luminal B -10% vs. 3%, luminal Her-2-Neu positive - 14% vs. 27%, classical her-2-Neu positive -21% vs. 22%, and triple negative -13% vs. 27%, correspondingly. Patients in the BM group were in average 6 years younger than patients in ‘pure’ BC group. In BMBC group median time of BM's development among Her-2-Neu (amplified Her-2-neu gene) patients was significantly shorter than that among Her-2-neu -negative (without amplification) patients: 40 months (range 8-288) versus 84 months (range 24-131 (p<0,05). The general survival time from first signs of BM was 8 months (ranges 0-89) in Her-2-neu- positive patients versus 13 months (ranges 0-72) in Her-2-neu -negative patients. Conclusions: Despite the fact that luminal A variant of BC is the most common one among primary tumors, in patients with BMBC triple negative and luminal Her-2-neu variants occurred more frequently. As age analysis showed, patients from BMBC group were younger than patients without BM. Therefore we believe that ‘brain metastatic’ carcinomas occur in a much younger population. Patients with BMBC Her-2-neu amplification have more aggressive development of disease and shorter survival time, than without Her-2-neu amplification. Citation Format: Daniil Rotin, Oxana Paklina, NV Lobanova, GL Kobyakov, Olga Potapova. Incidence of molecular variants with and without Her-2-Neu expression and amplification in brain metastases of breast carcinoma and its prognostic significance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5127. doi:10.1158/1538-7445.AM2013-5127

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Introduction: Breast carcinoma is the second common type of cancer metastasizing into the brain. Although the frequency of Her-2 positive primary breast tumors is no more than 30%, a higher occurrence of brain metastases has been reported for patients with positive Her-2/neu primary tumors. We investigated here expression of Her-2 protein and amplification of Her-2 gene in brain metastasis tissues of breast carcinoma patients. Patients and Methods: FFPE tumor tissues were obtained from consented patients treated with surgery at the NN Burdenko Neurosurgery Institute in 2004–2007. Total of 42 cases of brain metastases (BM) with breast tissue origin were evaluated. Solitary BM occurred in 59% (16/27) patients, while multiple metastatic lesions were observed in 41% (11/27) patients. The median age was 53 (range 29 − 73 years). Her-2/neu gene amplification was analyzed by fluorescent in situ hybridization (FISH). Levels of protein expression were detected by immunohistochemistry (IHC) according to the DAKO HercepTest grading system. Membranous staining intensiveness was estimated by a semi-quantitative method (from 0 to 3+). Cases with Her-2 IHC expression score of 2+ were reconfirmed by FISH analysis. Statistical analysis was done using STATISTICA 6.0 software. Results: Over-expression of Her-2 protein was observed in 50% (21/42) cases, while only in 7% (3/42) cases level of HER-2 protein was graded as negative (scores 0 and 1+). In 43% (18/42) cases IHC score was scored as 2+, and for those cases HER-2/neu gene amplification was performed using FISH analysis. Amplification of Her-2/neu was detected in 72% (13/18) cases in that group. Over-expression of Her-2/neu was similar in tissues from patients with a single metastatic lesion (63% (10/16) cases) compared to that of patients with multiple brain metastases (60% (25/42) of cases). Conclusions: Despite relatively lower incidence in primary tumors, Her-2/neu positive breast cancer tumors prevail in breast cancer brain metastases (about 60%), perhaps attributing to the higher malignant potential of such tumors. We found no difference in Her-2/neu protein expression levels in patients with single and multiple brain metastases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C41.