BackgroundCachexia is a metabolic syndrome that affects up to 50–80% of cancer patients. The pathophysiology is characterized by a variable combination of reduced food intake and abnormal metabolism, including systemic inflammation and negative protein and energy balance. Despite its high clinical significance, defined diagnostic criteria and established therapeutic strategies are lacking. The ‘omics’ technologies provide a global view of biological systems. We hypothesize that blood‐based metabolomics might identify findings in cachectic patients that could provide clues to gain knowledge on its pathophysiology, and eventually postulate new therapeutic strategies.MethodsThis is a cross‐sectional observational study in two cohorts of cancer patients, with and without cachexia. Patients were consecutively recruited from routine clinical practice of a General Oncology Department at ‘12 de Octubre’ University Hospital. Selected clinical and biochemical features were collected. Blood metabolite fingerprinting was performed using three analytical platforms, gas chromatography coupled to mass spectrometry (GC–MS), capillary electrophoresis coupled to mass spectrometry (CE–MS), and liquid chromatography coupled to mass spectrometry (LC–MS). Besides, we performed pathway‐based metabolite analyses to obtain more information on biological functions.ResultsA total of 15 subjects were included in this study, 8 cachectic and 7 non‐cachectic patients. Metabolomic analyses were able to correctly classify their samples in 80% (GC–MS), 97% (CE–MS), 96% [LC–MS (positive mode)], and 89% [LC–MS (negative mode)] of the cases. The most prominent metabolic alteration in plasma of cachectic patients was the decrease of amino acids and derivatives [especially arginine, tryptophan, indolelactic acid, and threonine, with 0.4‐fold change (FC) compared with non‐cachectic patients], along with the reduction of glycerophospholipids [mainly lysophosphatidylcholines(O‐16:0) and lysophosphatidylcholines(20:3) sn‐1, FC = 0.1] and sphingolipids [SM(d30:0), FC = 0.5]. The metabolite with the highest increase was cortisol (FC = 1.6). Such alterations suggest a role of the following metabolic pathways in the pathophysiology of cancer cachexia: arginine and proline metabolism; alanine, aspartate, and glutamate metabolism; phenylalanine metabolism; lysine degradation; aminoacyl‐tRNA biosynthesis; fatty acid elongation in mitochondria; tricarboxylic acids cycle; among others.ConclusionsThese findings suggest that plasma amino acids and lipids profiling has great potential to find the mechanisms involved in the pathogenesis of cachexia. Metabolic profiling of plasma from cancer patients show differences between cachexia and non‐cachexia in amino acids and lipids that might be related to mechanisms involved in its pathophysiology. A better understanding of these mechanisms might identify novel therapeutic approaches to palliate this unmet medical condition.

Neoadjuvant treatment allows us to improve surgical results and test new drugs. In recent years, there have been significant advances in the field of neoadjuvant treatment, including hormonal neoadjuvant therapy in luminal tumors, double blockade in HER2-positive tumors, and the use of platinum salts in triple-negative tumors.

PurposeMetastatic breast cancer (MBC) progressing after endocrine therapy frequently activates PI3K/AKT/mTOR pathway. The BOLERO-2 trial showed that everolimus-exemestane achieves increased progression free survival (PFS) compared with exemestane. However, there is great inter-patient variability in toxicity and response to exemestane-everolimus treatment. The objective of this study was to perform an exploratory study analyzing the implication of single nucleotide polymorphisms (SNPs) on outcomes from this treatment through a pharmacogenetic analysis.Patients and methodsBlood was collected from 90 postmenopausal women with hormone receptor-positive, HER2-negative MBC treated with exemestane-everolimus following progression after prior treatment with a non-steroidal aromatase inhibitor. Everolimus pharmacokinetics was measured in 37 patients. Twelve SNPs in genes involved in everolimus pharmacokinetics and pharmacodynamics were genotyped and associations assessed with drug plasma levels, clinically relevant toxicities (non-infectious pneumonitis, mucositis, hyperglycemia and hematological toxicities), dose reductions or treatment suspensions due to toxicity, progression free survival (PFS) and overall survival.ResultsWe found that CYP3A4 rs35599367 variant (CYP3A4*22 allele) carriers had higher everolimus blood concentration compared to wild type patients (P = 0.019). ABCB1 rs1045642 was associated with risk of mucositis (P = 0.031), while PIK3R1 rs10515074 and RAPTOR rs9906827 were associated with hyperglycemia and non-infectious pneumonitis (P = 0.016 and 0.024, respectively). Furthermore, RAPTOR rs9906827 was associated with PFS (P = 0.006).ConclusionsCYP3A4*22 allele influenced plasma concentration of everolimus and several SNPs in PI3K/AKT/mTOR pathway genes were associated with treatment toxicities and prognosis. These results require replication, but suggest that germline variation could influence everolimus outcomes in MBC.

Background: The TIS is a clinical research gene expression-based assay that enriches for response to anti-PD1 monotherapy in multiple cancer-types (Ayers et al. JCI 2017). However, the expression of the TIS in mTNBC and its relationship with other biological classifications and overall survival (OS) is currently unknown. Methods: A comprehensive RNA-based characterization of 45 patients with mTNBC treated at 2 SOLTI sites was performed. RNA from metastatic biopsies was analyzed on the nCounter system using the Breast Cancer 360TM panel, which includes 752 breast cancer-related genes, including the TIS and the PAM50 and TNBCtype subtype classifications. The 1ary objective was to estimate the proportion of TIS-high tumors (defined as a score above its median expression in the PanCancer TCGA dataset) within PAM50 Basal-like disease. 2ary objectives were 1) to explore TIS distribution across the other molecular subtypes, 2) to evaluate the distribution of the PAM50 and TNBCtype subtype classifications in mTNBC, 3) to explore the association between OS and TIS, subtypes and 38 additional signatures tracking multiple tumor biological processes. OS was defined as the time from the date of metastatic diagnosis to death or last follow-up. Descriptive statistics, log-rank tests and univariate cox models were performed using R code. Results: Most tumor samples (77.3%) were obtained at first recurrence or diagnosis of metastatic disease. Metastatic biopsies were obtained from 10 different sites, being skin (31.3%), breast (22.2%) and lung (8.9%) the most frequent. PAM50 subtype distribution was as follows: Basal-like (73.3%), Luminal A (13.3%), HER2-enriched (11.1%) and Luminal B (2.2%). Similarly, all the TNBCtype subtypes were identified: Mesenchymal (MSL, 48.8%), Basal-like Immune-activated (31.2%), Luminal Androgen Receptor (LAR, 15.6%) and Basal-like Immune-Suppressed (4.4%). The vast majority of non-Basal-like tumors were identified as LAR or MSL (81.8%). The proportion of TIS-high within Basal-like disease was 73% (95% confidence interval [CI] 59-84%) and similar to the proportion of TIS-high within TNBC from TCGA (70%, CI 61-78%). The proportion of TIS-high was similar across the PAM50 and TNBCtype molecular subtypes. The median OS was 25.3 months (CI 19.2-36.8). TIS, PAM50 and TNBCtype subtypes were not found associated with OS. Among the 41 biological classifications, expression of 6 signatures were found significantly associated with OS: CES (hazard ratio [HR] 0.44; p=0.015), Basal-like score (HR=5.52; p=0.011), FOXA1 (HR=0.83; p=0.014), mast cells (HR=0.77; p=0.017), differentiation score (HR=0.63; p=0.039) and Luminal A score (HR=0.27; p=0.039). Compared to tumors with a CES-low score, tumors with a CES-high score were found enriched for luminal-related genes, including AR. Conclusions:˜50% of mTNBC tumors are PAM50 Basal-like and are enriched for the TIS. Future studies should determine the ability of this biomarker to predict response to anti-PD1 monotherapy or in combination with chemotherapy. In addition, mTNBC with a high luminal-profile or CES might help identify patients who might benefit from anti-androgen therapies alone or in combination with immunotherapy. Citation Format: Pascual T, Pernaut C, Tolosa P, Galvan P, Bárcena C, Vidal M, Manso L, Adamo B, Dueñas M, Muñoz M, Chic N, Gonzalez-Farre B, Villagrasa P, Ciruelos E, Prat A. Tumor inflammation signature (TIS), intrinsic subtypes and chemo-endocrine score (CES) in metastatic triple-negative breast cancer (mTNBC): A SOLTI biomarker program study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-17.

INTRODUCTION: Although large randomized trials assessing the benefit of adjuvant trastuzumab in HER2-positive (HER2+) breast cancer have clearly demonstrated a significant improvement in long-term survival, it is necessary to know the impact of the use of trastuzumab adjuvant in the real life population, which includes patients frequently excluded from clinical trials, such as those with very small tumors without node involvement, or advanced age. The objective of this study is to describe the outcomes of women who received adjuvant trastuzumab for HER2+ cáncer since it was approved in 2006, compared with a previous cohort of HER2+ patients not treated with trastuzumab in 7 Spanish centers. METHODS: Women with newly diagnosed stage I-III, HER2+ breast cancer, between 1997 and 2015 were included in the study. Two cohorts were considered: The No-Trastuzumab cohort (No-T), between 1997 and 2005, and the Trastuzumab cohort (T) with trastuzumab-treated women between 2006 and 2015. Kaplan-Meier estimates were used to evaluate DFS and OS. Additionally, cohorts were analyzed by pathologic tumour size, lymph node involvement and hormonal receptor status to stratify outcome measures. RESULTS: A total of 2134 patients were identified. In 164 cases, data were insufficient or the follow-up incomplete. Therefore, the final analysis included 1970 patients, of whom 539 belong to the "No-T" cohort and 1431 to the "T" cohort. The median follow-up was 81 months. Median age: 53 years [22-98]. A total of 699 patients had T1 tumors [43% in the "No-T" cohort vs 33% in the "T" cohort]. 55% of the cases were N0 [58% and 54% in the "No-T" and "T" cohorts respectively]. The status of the hormonal receptors was well balanced between groups [36% ER negative in both]. Regarding the type of adjuvant treatment administered, in the "T" cohort more patients received adjuvant chemotherapy [65% vs 97%] and also in the “T” group combinations of taxanes and anthracyclines were more frequent [14% vs 72%]. The proportion of adjuvant endocrine therapy was similar in both groups [37% vs 34%]. In the “T” cohort, median Disease Free Survival (DFS) was not-reached, compared with 149 months in the “No-T” group. 5-year DFS was 83% vs 65% respectively [p<0.001]. 5-year DFS was also superior and statistically significant in all the subgroups analyzed, including patients with T1 tumors (87% vs 57%), N0 (87% vs 78%), patients T1N0 (88% vs 74%) and HR positive (86% vs 71%) or negative (78% vs 50%). Similarly, Overall Survival (OS) was increased in patients treated with Trastuzumab (median: 224 months vs not-reached, 5-year OS: 92% vs 75% [p <0.001].) 5-year OS was also statistically superior in the T1 subgroup (92% vs 72%), and N0 (95% vs 88%). [p<0.001 in all subanalysis]. CONCLUSIONS: Adjuvant treatment with Trastuzumab under conditions of real clinical practice in HER2+ early breast cancer, shows a highly significant benefit in terms of DFS and OS, regardless of the stage of the disease or other clinical variables. A very important benefit was reached in patients with small tumors, node-negative disease, or both conditions (T1N0). The benefit was also obtained regardless of the expression of hormonal receptors. Citation Format: Rodriguez CA, Garcia-Gomez J, Ribelles N, Gavila J, Pernas S, Rodriguez-Lescure A, Urrutikoetxea A, Pernaut C, Lopez A, Garcia-Mata J. Impact of the adjuvant treatment with trastuzumab in HER2 positive breast cancer in the real-world setting. Analysis of two cohorts (1997-2005/2006-2015) in 1970 patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-13-04.