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PDF file - 45K, Summary of adverse events suspected to be study-drug related by grade (safety set).

PDF file - 67K, Bayesian logistic regression model: dose-response curve and model inference results at the time of determination of the recommended Phase II dose.

Supplementary Data from Novel Inhibitors of Fatty Acid Synthase with Anticancer Activity

PDF file - 65K, Criteria for defining dose-limiting toxicities.

Purpose: Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway activation in patients with HER2-positive (HER2+) breast cancer has been implicated in de novo and acquired trastuzumab resistance. The purpose of this study was to determine the clinical activity of the PI3K inhibitor buparlisib (BKM120) in patients with HER2+ advanced/metastatic breast cancer resistant to trastuzumab-based therapy.Experimental Design: In the dose-escalation portion of this phase I/II study, patients with trastuzumab-resistant locally advanced or metastatic HER2+ breast cancer were treated with daily oral doses of buparlisib and weekly intravenous trastuzumab (2 mg/kg). Dose escalation was guided by a Bayesian logistic regression model with overdose control.Results: Of 18 enrolled patients, 17 received buparlisib. One dose-limiting toxicity of grade 3 general weakness was reported at the 100-mg/day dose level (the single-agent maximum tolerated dose) and this dose level was declared the recommended phase II dose (RP2D) of buparlisib in combination with trastuzumab. Common (>25%) adverse events included rash (39%), hyperglycemia (33%), and diarrhea (28%). The pharmacokinetic profile of buparlisib was not affected by its combination with trastuzumab. At the RP2D, there were two (17%) partial responses, 7 (58%) patients had stable disease (≥6 weeks), and the disease control rate was 75%. Pharmacodynamic studies showed inhibition of the PI3K/AKT/mTOR and RAS/MEK/ERK pathways.Conclusions: In this patient population, the combination of buparlisib and trastuzumab was well tolerated, and preliminary signs of clinical activity were observed. The phase II portion of this study will further explore the safety and efficacy of this combination at the RP2D. Clin Cancer Res; 20(7); 1935–45. ©2014 AACR.

Purpose: Fatty acid synthase (FASN) is overexpressed in human breast carcinoma. The natural polyphenol (−)-epigallocatechin-3-gallate blocks in vitro FASN activity and leads to apoptosis in breast cancer cells without any effects on carnitine palmitoyltransferase-1 (CPT-1) activity, and in vivo, does not decrease body weight. We synthesized a panel of new polyphenolic compounds and tested their effects on breast cancer models.Experimental Design: We evaluated the in vitro effects of the compounds on breast cancer cell growth (SK-Br3, MCF-7, and MDA-MB-231), apoptosis [as assessed by cleavage of poly(ADP-ribose) polymerase], cell signaling (HER2, ERK1/2, and AKT), and fatty acid metabolism enzymes (FASN and CPT-1). In vivo, we have evaluated their antitumor activity and their effect on body weight in a mice model of BT474 breast cancer cells.Results: Two compounds potently inhibited FASN activity and showed high cytotoxicity. Moreover, the compounds induced apoptosis and caused a marked decrease in the active forms of HER2, AKT, and ERK1/2 proteins. Interestingly, the compounds did not stimulate CPT-1 activity in vitro. We show evidence that one of the FASN inhibitors blocked the growth of BT474 breast cancer xenografts and did not induce weight loss in vivo.Conclusions: The synthesized polyphenolic compounds represent a novel class of FASN inhibitors, with in vitro and in vivo anticancer activity, that do not exhibit cross-activation of β-oxidation and do not induce weight loss in animals. One of the compounds blocked the growth of breast cancer xenografts. These FASN inhibitors may represent new agents for breast cancer treatment. (Clin Cancer Res 2009;15(24):7608–15)

PDF file - 38K, Patient disposition (full analysis set).

PDF file - 48K, Exposure to buparlisib and trastuzumab (safety set).

PDF file - 62K, Summary of buparlisib pharmacokinetic parameters.

PDF file - 72K, RANK overexpression induces mammary stem markers

PDF file - 172K, RANK overexpression promotes growth, invasive changes and metastasis in cells with non-functional BRCA1

PDF file - 114K, FL-RANK cells grow in the absence of EGF and do not form tumors in vivo.

PDF file - 91K, RANK is expressed and active in MCF10A cells

PDF file - 89K, RANK/RANKL expression significantly associates with tumor subtype and lymph node metastasis

PDF file - 113K, RANK expression induces EMT in MCF10A and in HMECS immortalized with telomerase

PDF file - 167K

Background: Cyclin-dependent kinases 4 and 6 inhibitors in combination with endocrine therapy frequently lead to a complete cell-cycle arrest (CCCA) in luminal EBC. However, the rates of pathological complete response (pCR) or Residual Cancer Burden (RCB) 0-I are modest. The effect of this treatment in terms of molecular downstaging as assessed by a genomic signature more refined than Ki67 remains undetermined. We aimed to assess the biological and clinical activity of letrozole plus palbociclib as neoadjuvant treatment in HR-positive/HER2-negative EBC pts with an Oncotype DX RS ≥18. Methods: DxCARTES was a multicenter, open-label, non-comparative, phase 2 trial across 16 hospitals in Spain. Participants were pre- and post-menopausal women aged ≥18 years with centrally confirmed HR-positive/HER2-negative, Ki67≥20%, stage II-IIIB EBC with a RS ≥18. Eligible pts with baseline RS 18-25 (cohort A) and RS 26-100 (cohort B) received six 28-days cycles of letrozole (2.5 mg QD), ± goserelin if premenopausal, plus palbociclib (125 mg QD, 3/1 schedule) before surgery. Tumor samples were prospectively collected at baseline and surgery for Ki67 and RS assessments. The coprimary endpoint was the proportion of pts in either cohort who achieved RS ≤25 or a pCR (ypT0/is ypN0) at surgery. Secondary endpoints included analysis of RCB, preoperative endocrine prognostic index (PEPI), CCCA (Ki67 Citation Format: Antonio Llombart-Cussac, Ángel Guerrero-Zotano, Manuel Ruiz, Begoña Bermejo, Miguel Gil-Gil, Juan de la Haba, Emilio Alba, Vanesa Quiroga, Vicente Carañana, Ander Urruticoechea, Serafín Morales, Meritxell Bellet, Antonio Antón, José Manuel Pérez-García, María Fernández-Abad, Sonia Servitja, Pedro Sánchez-Rovira, Sofia Braga, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortes. Neoadjuvant letrozole plus palbociclib in patients (pts) with hormone receptor (HR)-positive/HER2-negative early breast cancer (EBC) with baseline Ki67 ≥20% and an Oncotype DX Breast Recurrence Score® result (RS) ≥18: DxCARTES [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-12.

Background. Neoadjuvant endocrine therapy (NET) in luminal breast cancer (LBC) is the perfect scenario for real-time evaluation of the biological and molecular changes that occur after estrogenic deprivation. This evaluation is mainly performed in surgical specimens after NET and has been used as a research tool to obtain prognostic and predictive information using tumor response to decide adjuvant treatment. Nevertheless, there are not many validated biomarkers in this setting to predict response beyond Ki67 levels and modified Preoperative Prognostic Index (mPEPI score) after treatment. Hence, the aim of this study is to determine if changes in mRNA-based PAM50 analysis (intrinsic subtype) after NET in LBC correlate with such biomarkers. Methods. We collected a series of postmenopausal ER+/HER2- breast cancer patients (n=58) treated for at least 4 months with NET before surgery. Next, we performed gene expression analysis by PAM50 accompanied by pathological characterization of surgical tumor specimens and immunohistochemistry characterization of ER and Ki67 levels, both at diagnosis and in surgery specimen. Finally, we studied the association of our results with clinical and histopathological features and with validated biomarkers for endocrine response, such as mPEPI score and changes in Ki67 levels. Results. The distribution of changes in intrinsic subtype determined by PAM50 after NET is presented in Table 1. We observed that tumors that changed from luminal to a normal intrinsic subtype showed larger changes in Ki67 levels after NET and reduced percentage of Ki67 positive cells at surgery, compared to those that presented a luminal persistent status: both analysis P Table 1.- Intrinsic subtypes determined by PAM50 in samples pre and post NETPAM50 PREPAM50 POSTNO.%PERSISTANT LUMINAL STATUSCHANGE FROM LUMINAL TO A NOLMAL INTRINSIC SUBTYPELumALumA2136YESLumANormal1526YESLumALumB35YESLumBLumA610YESLumBNormal35YESLumBLumB59YESHER2HER223NANAHER2LumA12NANALumAHER212NANANormalNormal12NANATOTAL58100Lum=LuminalNA= Not applicable Citation Format: Joanna Ines Lopez Velazco, María Otaño, Inazio Lacambra, Kepa Elorriaga, Ainhara Lahuerta, Ana Martínez, Virginia Segur, Sara Manzano, Aleix Prat, María Caffarel, Ander Urruticoechea. Conversion from luminal to normal intrinsic subtype by PAM50 after neoadjuvant endocrine therapy is associate with biomarkers of good prognosis in luminal breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-15-01.

Neoadjuvant endocrine therapy in oestrogen receptor (ER) positive HER2 negative breast cancer allows real-time evaluation of drug efficacy as well as investigation of the biological and molecular changes that occur after estrogenic deprivation. Clinical and pathological evaluation after neoadjuvant endocrine therapy may be used to obtain prognostic and predictive information of tumour response to decide adjuvant treatment. In this setting, clinical scales developed to evaluate response after neoadjuvant chemotherapy are not useful and there are not many validated biomarkers to assess response to neoadjuvant endocrine therapy beyond Ki67 expression and preoperative prognostic index (PEPI) score. In this prospective study, we extensively analysed radiological (by ultrasound and magnetic resonance imaging) and pathological tumour response of 104 postmenopausal patients with ER+/HER2-resectable breast cancer, treated with neoadjuvant endocrine treatment for a mean of 7 months prior to surgery. Our results show that radiological evaluation by both USS and MRI underestimate pathological tumour size, although they support the use of MRI over USS to clinically assess tumour response. In addition, we propose that the tumour cellularity size, calculated as the product of the percentage of residual tumour cellularity in the surgical specimen and the tumour pathological size, could become a new tool to standardize response assessment to NET given its good correlation with and potential added value to existing biomarkers. Our findings shed light on the dynamics of tumour response to neoadjuvant endocrine therapy, challenge the paradigm of the ability of NET to decrease surgical volume and point to the utility of the tumour cellularity size to quantify the scattered tumour response usually produced by endocrine therapy.

The tumor microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumor progression. The contribution of stromal cells to the reprogramming of the TME is not well understood. Here, we provide evidence of the role of the cytokine oncostatin M (OSM) as central node for multicellular interactions between immune and nonimmune stromal cells and the epithelial cancer cell compartment. OSM receptor (OSMR) deletion in a multistage breast cancer model halted tumor progression. We ascribed causality to the stromal function of the OSM axis by demonstrating reduced tumor burden of syngeneic tumors implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumors revealed that OSM expression was restricted to myeloid cells, whereas OSMR was detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprogrammed fibroblasts to a more contractile and tumorigenic phenotype and elicited the secretion of VEGF and proinflammatory chemokines CXCL1 and CXCL16, leading to increased myeloid cell recruitment. Collectively, our data support the notion that the stromal OSM/OSMR axis reprograms the immune and nonimmune microenvironment and plays a key role in breast cancer progression., This work was funded by Spanish Ministry of Science and Innovation - ISCIII (PI15/00623, PI18/00458, PI21/01208, CP18/00076, and FI19/00193); European Regional Development (FEDER) funds; Basque Department of Health (2017111011); Fundación SEOM (Beca SEOM-Font Vella); Fundación Gangoiti; and Ikerbasque Basque Research Foundation. The group also received funds from the breast cancer patient’s charity Katxalin and from Roche Farma S.A. AMA and AA are funded by Basque Government Doctoral Training Grants. JILV is funded by an AECC PhD Fellowship. FVM is supported by the Career Development Fellowship from the Cancer Institute New South Wales (2019/CDF002). AP’s research is funded by the European Research Council (ERC, ERC-2018-StG 804236-NEXTGEN-IO), and by the Spanish Ministry of Science and Innovation (PID2019-107956RA-I00 and RYC2018-024183-I). AC’s research is supported by the Basque Department of Industry, Tourism and Trade (Elkartek); the MICINN (PID2019-108787RB-I00 [FEDER/EU]; Excellence Network (SAF2016-81975-REDT); European Training Networks Project (H2020-MSCA-ITN-308 2016 721532); the AECC (GCTRA18006CARR), Vencer el Cáncer Foundation; La Caixa Foundation (ID 100010434), under the agreement LCF/PR/HR17/; and the ERC (Consolidator Grant 819242). CIBERONC was cofunded with FEDER funds and funded by ISCIII. DGO is supported by a Cancer Council NSW project grant (RG18-03) and the National Breast Cancer Foundation Elaine Henry Fellowship (IIRS-21-096). FC is funded by Institute of Cancer Research, Spanish Ministry of Science and Innovation (RYC-2016-20352 and RTI2018-096778-A-I00); Asociacion Española Contra el Cancer (LAB-AECC, LABAE19044CALV); and BBVA Leonardo Awards (IN[19]_BBM_BAS_0076).

Background: Neoadjuvant endocrine therapy (NET) is an approach that allows real-time evaluation of drug efficacy as well as investigation of the biological and molecular changes that occur after estrogenic deprivation. This evaluation is mainly performed in surgical specimens after NET and it has been used as a research tool to obtain prognostic and predictive information using tumour response to decide adjuvant treatment. In this setting, there are not many validated biomarkers to predict response beyond Ki67 expression and Preoperative Prognostic Index (PEPI score) in NET. The aim of this study is to determine if the tumour cellularity size (TCS) in surgical specimen after NET correlates with PEPI score and Ki67 expression. Methods: Retrospective study of postmenopausal patients with estrogen receptor (ER) positive/HER2 negative resectable breast cancer, treated with an aromatase inhibitor for at least 4 months prior to surgery. Pathological characterization of tumour specimens: Evaluation of the percentage of residual tumour cellularity of formalin fixed paraffin embedded surgical specimens and immunohistochemistry characterization of ER and Ki67. Tumour cellularity size: calculated by combining the percentage of residual tumour cellularity and tumour pathological size. Results: N=104. Tumour characteristics at surgery and breakdown for the calculated PEPI score: table 1. Correlation between the percentage of Ki67 positive cells at surgery and TCS: (r=0.2503) p=0.04 (95% CI, 0.0014 to 0.4700). Correlation between TCS and PEPI score: (r=0.2582) p=0.05 (95% CI, -0.0131 to 0.4940). Conclusions: Tumour cellularity size is a promising biomarker to determine response and prognosis after NET. There is a need to find other biomarkers to predict response after NET. Table 1Pathology/Biomarker statusPEPI score RFS pointsNo. of patientspTNot available (NA)1pT1/T20102pT3/T431pNNA7Negative075Positive322KI67 levelNA10%-2.7%039>2.7%-7.3%131>7.3%-19.7%119>19.7%-53.1%213>53.1%31ER-status Allred scoreNA120-2303-8092PEPI scoreNA190281342533495561PEPI groupNot calculated19I (0 score)28II (1-3 score)42III (≥4 score)15 Citation Format: Joanna Ines Lopez Velazco, María Otaño, Lide Larburu, Ainhara Lahuerta, Kepa Elorriaga, Virginia Segur, Juan Carlos Irizabal, Ana Martínez, Lourdes Jáuregui, Maria M. Caffarel, Ander Urruticoechea. Tumour cellularity size as a biomarker to predict response after neoadjuvant endocrine therapy: Correlation analysis between Ki67 expression and PEPI score [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-39.

Purpose In the absence of head-to-head trial data, network meta-analysis (NMA) was used to compare trastuzumab emtansine (T-DM1) with other approved treatments for previously treated patients with unresectable or metastatic HER2-positive breast cancer (BC). Methods Systematic reviews were conducted of published controlled trials of treatments for unresectable or metastatic HER2-positive BC with early relapse (≤ 6 months) following adjuvant therapy or progression after trastuzumab (Tras) + taxane published from January 1998 to January 2018. Random-effects NMA was conducted for overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety endpoints. Results The NMA included regimens from seven randomized controlled trials: T-DM1 and combinations of Tras, capecitabine (Cap), lapatinib (Lap), neratinib, or pertuzumab (Per; unapproved). OS results favored T-DM1 over approved comparators: hazard ratio (HR) (95% credible interval [95% CrI]) vs Cap 0.68 (0.39, 1.10), LapCap 0.76 (0.51, 1.07), TrasCap 0.78 (0.44, 1.19). PFS trends favored T-DM1 over all other treatments: HR (95% CrI) vs Cap 0.38 (0.19, 0.74), LapCap 0.65 (0.40, 1.10), TrasCap 0.62 (0.34, 1.18); ORR with T-DM1 was more favorable than with all approved treatments. In surface under cumulative ranking curve (SUCRA) analysis T-DM1 ranked highest for all efficacy outcomes. Discontinuation due to adverse events was less likely with T-DM1 than with all comparators except neratinib. In general, gastrointestinal side effects were less likely and elevated liver transaminases and thrombocytopenia more likely with T-DM1 than with comparators. Conclusions The efficacy and tolerability profiles of T-DM1 are generally favorable compared with other treatments for unresectable or metastatic HER2-positive BC.

Background: Modulation of estrogen activity and/or synthesis is the mainstay therapeutic strategy in the treatment of ER positive breast cancer. However, despite the effectiveness of available endocrine therapies, many patients ultimately relapse or develop resistance to these agents via estrogen-dependent and estrogen-independent mechanisms, including mutations in ESR1 affecting the ER ligand binding domain that drive ER-dependent transcription and proliferation in the absence of estrogen. Based on preclinical and clinical data, SERDs are expected be effective in patients harboring ESR1 mutations. Biomarker analysis was performed on plasma and tumor samples from the Phase I study of GDC-0927 in metastatic breast cancer (Dickler et al, SABCS 2017) with the goal of evaluating activity in both ESR1 mutant and wildtype tumors, and to assess ER pathway modulation. Methods: Hotspot mutations in ESR1, PIK3CA, and AKT1 were analyzed in baseline, on-treatment and end of treatment plasma derived circulating tumor DNA (ctDNA) using the BEAMing assay in patients treated at multiple dose levels of GDC-0927. A subset of samples was analyzed with Foundation Medicine's next generation sequencing ctDNA assay (FACT), which covers genomic alterations in 62 commonly altered genes. Paired pre- and on-treatment biopsies were collected to assess ER pathway modulation. ER, PR, and Ki67 protein levels were analyzed by immunohistochemistry. Gene expression analysis was performed using Illumina's RNA Access library preparation kit followed by paired-end (2x50b, 50M reads) sequencing on the HiSeq. Results: Baseline and on-treatment plasma samples were available for 40 patients. ESR1 and PIK3CA mutations were observed in 52% and 33% of patient baseline samples, respectively (BEAMing method). Mutant allele frequencies (MAF) generally declined in the first on-treatment samples collected for both ESR1 (16 out of 21 samples) and PIK3CA (7 out of 12 samples). The majority of the reductions were greater than 95% relative to baseline. Increases in ESR1 MAFs were observed in later time-points and were not associated with any particular ESR1 mutation. There were six instances for which an ESR1 mutation was detected in an on-treatment sample that was not detected in the baseline sample, three at L536P and one each at D538G, L536H, and S463P, and four out of six with MAFs close to the limit of detection. The FACT assay also detected alterations in CDH1, NF1, PTEN, and TP53 in baseline samples. The relationship between MAF changes and clinical benefit to GDC-0927 will be presented. A predefined, experimentally-derived set of ER target genes were evaluated in pre- and on-treatment tumor biopsy pairs from six patients. Four of the six patients showed evidence of suppression in ER pathway activity, one patient treated at the 1000 mg dose level and three at the 1400 mg dose. The degree of pathway suppression was associated with pre-treatment pathway levels and decreases of ER and Ki67 protein levels. Conclusions: We report here evidence of consistent reduction of ESR1 and PIK3CA ctDNA in patients treated with GDC-0927. ER pathway suppression was observed at both the transcript and protein level confirming pharmacodynamic activity of the SERD. Citation Format: Spoerke JM, Daemen A, Chang C-W, Giltnane J, Metcalfe C, Dickler MN, Bardia A, Perez Fidalgo JA, Mayer IA, Boni V, Winer EP, Hamilton EP, Bellet M, Urruticoechea A, Gonzalez Martin A, Cortes J, Martin M, Gates M, Cheeti S, Fredrickson J, Wang X, Friedman LS, Liu L, Li R, Chan IT, Mueller L, Milan S, Lauchle J, Humke EW, Lackner MR. Phamacodynamic and circulating tumor DNA evaluation in a phase I study of GDC-0927, a selective estrogen receptor antagonist/ degrader (SERD) [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 P5-11-01.

BACKGROUND:Triple negative breast cancer (TNBC) has poor prognosis, lack of targeted therapies and are often refractory to conventional chemotherapy treatments. Therefore, finding new therapeutic targets for those tumours is an unmet need with high clinical impact. In this context, Oncostatin M receptor (OSMR) is a promising therapeutic target as it is over-expressed in this tumour subtype and its activation promotes invasiveness (Guo L, et al. 2013 Oncogene; West NR, et al.2014 Oncogene). We previously showed that OSMR is frequently copy-number gained and over-expressed in squamous cell carcinoma, where it induces migration, invasion and metastasis (Caffarel MM, et al 2013 Journal of Pathology; Caffarel MM, et al 2014 Journal of Pathology; Kucia-Tran JA, et al. 2016 Brit J Cancer; Kucia-Tran JA, et al 2018 Journal of Pathology). We now investigate the role of OSMR in breast cancer progression. METHODS: To address this issue we use a wide array of tools including in vitro cell cultures and in vivo models. The expression of OSMR pathway was analysed in FFPE samples and large datasets of publicly available breast cancer samples (METABRIC, n=1462; and TCGA, n=547). RESULTS: OSMR and its ligand Oncostatin M (OSM) are over-expressed in basal tumours, where they associate with shorter overall survival (p=0.015). While OSMR is expressed by breast cancer cells and cancer associated fibroblasts, the main source of OSM seems to be primarily macrophages. OSM treatment of breast cancer cells induces the expression of important mediators of angiogenesis and invasion. Importantly, OSMR activation accelerates tumour onset, tumour growth and metastasis in orthotopic xenografts in nude mice. CONCLUSIONS: Our results support that OSMR pathway may have an important role in the initiation and progression of breast cancer and that it could be a promising candidate for therapeutic targeting in TNBC. OSMR could be blocked by antibody based inhibition, strategy that has had a major impact on breast cancer. Citation Format: Alvarez I, Araujo A, Abaurrea A, Rezola R, Urruticoechea A, Lawrie C, Caffarel MM. New targets in triple negative breast cancer: Role of Oncostatin M receptor pathway [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 P2-06-16.

Cancer cells are constantly communicating with the surrounding tumour microenvironment (TME) and they hijack physiological cell interactions to overcome immune system surveillance and promote cancer progression1,2. However, the contribution of stromal cells to the reprogramming of the TME is not well understood. In this study we provide unprecedented evidence of the role of the cytokine Oncostatin M (OSM) as central node for multicellular interactions between immune and non-immune stroma and the epithelial compartment. We show that stromal expression of the OSM:Oncostatin M Receptor (OSMR) axis plays a key role in breast cancer progression. OSMR deletion in a multistage breast cancer model delays tumour onset, tumour growth and reduces metastatic burden. We ascribed causality to the stromal function of OSM axis by demonstrating reduced tumour burden of syngeneic tumours implanted in mice. Single-cell and bioinformatic analysis of murine and human breast tumours revealed that the expression of OSM signalling components is compartmentalized in the tumour stroma. OSM expression is restricted to myeloid cells, whereas OSMR expression is detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprograms fibroblasts to a more contractile and pro-tumorigenic phenotype, elicits the secretion of VEGF and pro-inflammatory chemokines (e.g. CXCL1 and CXCL16), leading to increased neutrophil and macrophage recruitment. In summary, our work sheds light on the mechanism of immune regulation by the tumour microenvironment, and supports that targeting OSM:OSMR interactions is a potential therapeutic strategy to inhibit tumour-promoting inflammation and breast cancer progression.

Red blood cell (RBC) membrane can reflect fatty acid (FA) contribution from diet and biosynthesis. In cancer, membrane FAs are involved in tumorigenesis and invasiveness, and are indicated as biomarkers to monitor the disease evolution as well as potential targets for therapies and nutritional strategies. The present study provides RBC membrane FA profiles in recently diagnosed breast cancer patients before starting chemotherapy treatment. Patients and controls were recruited, and their dietary habits were collected. FA lipidomic analysis of mature erythrocyte membrane phospholipids in blood samples was performed. Data were adjusted to correct for the effects of diet, body mass index (BMI), and age, revealing that patients showed lower levels of saturated fatty acids (SFA) and higher levels of monounsaturated fatty acid, cis-vaccenic (25%) than controls, with consequent differences in desaturase enzymatic index (∆9 desaturase, &ndash, 13.1%). In the case of polyunsaturated fatty acids (PUFA), patients had higher values of &omega, 6 FA (C18:2 (+11.1%), C20:4 (+7.4%)). RBC membrane lipidomic analysis in breast cancer revealed that &omega, 6 pathways are favored. These results suggest new potential targets for treatments and better nutritional guidelines.

Up-regulation of the Hedgehog (Hh) pathway is implicated in the genesis of a wide range of tumors including triple negative breast cancer (TNBC). Sonidegib is a potent and selective oral inhibitor of Smo, a key component of the Hh signaling pathway. We designed a phase I clinical study to explore the combination of sonidegib plus docetaxel (fixed dose at 75 mg/m2) in advanced TNBC patients. The primary objective was to ascertain the combination’s maximum tolerated dose and the recommended phase II dose (RP2D), based on dose limiting toxicities (DLTs) in the first 2 cycles. A standard “3 + 3” design was followed including three dose levels (DL) of sonidegib: 400 mg (DL1), 600 mg (DL2), and 800 mg (DL3). Twelve patients were included. Sonidegib 800 mg orally q.d. plus docetaxel 75 mg/m2 given intravenously on day 1 of 21-day cycles was established as the RP2D. No DLTs were observed at any DL. The median number of administered cycles at DL3 was 8 (range: 6 to 9). Grade 3 adverse events (AEs) at DL3 were neutropenia (66.7%), CPK increase (33.3%), leukopenia (33.3%), and paresthesia (33.3%), grade 4 AEs were not reported at this DL. At the RP2D, the combination showed antitumor activity in three out of 10 patients with measurable disease. Median time to progression for the overall study was 42.5 days (95% Confidence Interval: 29–155), and 188 days at DL3. No drug-to-drug interactions between sonidegib and docetaxel were found in the PK assessment. Trial Registration: EudraCT study number: 2013–001750-96. Study GEICAM/2012–12. TRIAL REGISTRATION: EudraCT study number: 2013-001750-96. Study GEICAM/2012-12. ClinicalTrials.gov: NCT02027376

Background: Modulation of estrogen activity and/or synthesis is the mainstay therapeutic strategy in the treatment of ER+ BC. However, despite the effectiveness of available endocrine therapies, many patients ultimately relapse or develop resistance to these agents via estrogen-dependent and estrogen-independent mechanisms, including mutations in ESR1 affecting the ER ligand binding domain that drive ER-dependent transcription and proliferation in the absence of estrogen. ER antagonists that are efficacious against ligand-dependent and ligand-independent, constitutively active ESR1 mutant tumors may be of substantial therapeutic benefit. GDC-0927 (formerly known as SRN-927) is a novel, potent, non-steroidal, orally bioavailable, selective ER antagonist/ER degrader (SERD) that induces tumor regression in ER+ BC patient-derived xenograft models. Methods: A phase I dose escalation study with 3+3 design was conductedin postmenopausal women with ER+ (HER2-) metastatic BC (progressing ≥ 6 months on endocrine therapy and with ≤ 2 prior chemotherapies in the advanced or metastatic setting) to determine the safety, pharmacokinetics (PK) and the recommended Phase 2 dose (RP2D) of GDC-0927. Pharmacodynamic (PD) activity was assessed with [18F]-fluoroestradiol (FES)-PET scans. Plasma PK samples (after single dose and at steady state), CT scans, and when feasible, pre and on-study tumor biopsies were obtained Results: From March 16, 2015 to March 17, 2017 patients (pts) with a median age of 53 years (range 44-69) and a median number of prior therapies for MBC 4 (range 1-7) were enrolled at 3 total daily dose levels (600, 1000, 1400 mg) once daily (QD) given orally with fasting (n = 12). Increases in GDC-0927 exposure were approximately dose proportional. Treatment related adverse events (AEs) were all grade 1 or 2. The most common treatment-related AEs were nausea (54%, n = 7), diarrhea (46%, n = 6), elevated aspartate aminotransferase (39%, n = 5) and anemia, constipation, (each 31%, n = 4). Treatment interruption was required for 2 pts due to nausea and vomiting. Of those pts with FES-PET avid disease at baseline (9 of 12), all post-therapy scans showed complete or near complete (> 90%) suppression of FES uptake to background levels, including pts with ESR1 mutations. Evidence of reduced ER levels and Ki67 staining was observed in on-treatment biopsies. Five of 12 pts (1 at 600 mg and 4 at 1400 mg) were on study ≥ 24 weeks (CBR = 41.6 %) with the best overall response of stable disease with 1 patient (ESR1 mt+ D538G) on study for over 490 days. There were no dose limiting toxicities and no SAEs related to study drug. R2PD was 1400 mg and was selected for single arm dose-expansion which is now complete with last patient enrolled on March 17, 2017. Updated results from dose-escalation and dose-expansion will be presented at the meeting (N = 43). Conclusions: GDC-0927 appears well-tolerated to date with PK exposure supporting QD dosing, evidence of robust PD target engagement, and encouraging anti-tumor activity in heavily pretreated pts with advanced or metastatic ER+ BC, including pts with ESR1 mutations. Citation Format: Dickler MN, Villanueva R, Perez Fidalgo JA, Mayer IA, Boni V, Winer EP, Hamilton EP, Bellet M, Urruticoechea A, Gonzalez-Martin A, Cortes J, Martin M, Giltnane J, Gates M, Cheeti S, Fredrickson J, Wang X, Friedman LS, Spoerke JM, Metcalfe C, Liu L, Li R, Morley R, McCurry U, Chan IT, Mueller L, Milan S, Lauchle J, Humke EW, Bardia A. A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-0927, in postmenopausal women with estrogen receptor positive (ER+) HER2-negative metastatic breast cancer (BC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-10.

PURPOSE: A Phase Ib study in patients with trastuzumab-resistant, human epidermal growth factor receptor-2- (HER2)-positive advanced breast cancer defined the recommended Phase II dose of buparlisib as 100 mg/day in combination with 2 mg/kg weekly trastuzumab, and reported preliminary signs of clinical activity. Here we present results from the Phase II portion. METHODS: Patients with trastuzumab-resistant, HER2-positive advanced breast cancer received buparlisib plus trastuzumab. Study endpoints included safety/tolerability and antitumour activity. The study was extended to include a Phase Ib dose-escalation phase, in which patients with progressive brain metastases also received capecitabine. RESULTS: In the Phase II portion, of 50 patients treated with buparlisib and trastuzumab, the most common (≥ 30%) all-grade adverse events (AEs) were diarrhoea (54%), nausea (48%), decreased appetite, increased alanine aminotransferase (36% each), increased aspartate aminotransferase (34%), fatigue, rash (32% each), cough and hyperglycemia (30% each). One (2%) patient achieved complete response and four (8%) patients had confirmed partial responses [PR; including two patients with phosphatidylinositol 3-kinase (PI3 K) pathway-activated tumours]. Overall response rate (ORR) was 10%: the primary endpoint (ORR ≥ 25%) was therefore not met. In the Phase Ib portion, all patients with measurable brain lesions at baseline showed tumour shrinkage to some degree; due to low enrollment, maximum tolerated dose of buparlisib in combination with trastuzumab and capecitabine was not determined. CONCLUSION: Buparlisib plus trastuzumab, as a chemotherapy-free regimen, demonstrated an acceptable safety profile but limited efficacy in patients with heavily pretreated, trastuzumab-resistant HER2-positive breast cancer, and in patients with progressive brain metastases also receiving capecitabine.

Purpose To assess the efficacy and safety of trastuzumab plus capecitabine with or without pertuzumab in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer who experienced disease progression during or after trastuzumab-based therapy and received a prior taxane. Patients and Methods Patients were randomly assigned to arm A: trastuzumab 8 mg/kg → 6 mg/kg once every 3 weeks plus capecitabine 1,250 mg/m2 twice a day (2 weeks on, 1 week off, every 3 weeks); or arm B: pertuzumab 840 mg → 420 mg once every 3 weeks plus trastuzumab at the same dose and schedule as arm A plus capecitabine 1,000 mg/m2 on the same schedule as arm A. The primary end point was independent review facility–assessed progression-free survival (IRF PFS). Secondary end points included overall survival (OS) and safety. Hierarchical testing procedures were used to control type I error for statistical testing of IRF PFS, OS, and objective response rate. Results Randomly assigned (intent-to-treat) populations were 224 and 228 patients in arms A and B, respectively. Median IRF PFS at 28.6 and 25.3 months’ median follow-up was 9.0 v 11.1 months (hazard ratio, 0.82; 95% CI, 0.65 to 1.02; P = .0731) and interim OS was 28.1 v 36.1 months (hazard ratio, 0.68; 95% CI, 0.51 to 0.90). The most common adverse events (all grades; incidence of ≥ 10% in either arm and ≥ 5% difference between arms) were hand-foot syndrome, nausea, and neutropenia in arm A, and diarrhea, rash, and nasopharyngitis in arm B. Conclusion The addition of pertuzumab to trastuzumab and capecitabine did not significantly improve IRF PFS. An 8-month increase in median OS to 36.1 months with pertuzumab was observed. Statistical significance for OS cannot be claimed because of the hierarchical testing of OS after the primary PFS end point; however, the magnitude of OS difference is in keeping with prior experience of pertuzumab in metastatic breast cancer. No new safety signals were identified.

[Background]: An important proportion of HER2-positive metastatic breast cancer patients do not respond to trastuzumab. The combination of dasatinib and trastuzumab has shown to be synergistic in preclinical models., [Methods]: We conducted a phase II trial combining dasatinib 100 mg once daily with trastuzumab 2 mg/kg and paclitaxel 80 mg/m2 weekly. Primary objective was objective response rate (ORR) and secondary included safety, other efficacy parameters and pharmacodynamics in tumour tissue, blood samples and skin biopsies., [Results]: From June 2013 to December 2015, 29 patients were included. Median number of cycles was 12 (1–49). Only 6 patients discontinued due to adverse events. ORR was 79.3% (95% CI 60.3–92), clinical benefit rate 82.8% (95% CI 64.2–94.2). Median time to progression 23.9 months (95% CI 14.9–not reached [NR]), median progression-free survival 23.9 months (95% CI 10.3–NR). No grade 4 toxicity was seen. Grade 3 toxicities included: ejection fraction decrease, neutropenia, hyponatremia, fatigue and sensory neuropathy and one left ventricular systolic dysfunction. Phosphorylated (p)-SRC was reduced in peripheral blood mononuclear cells. Phosphorylated SRC, ERK and AKT were also reduced in epidermal keratinocytes., [Conclusions]: Dasatinib can be safely combined with trastuzumab and paclitaxel. The combination is active with an ORR of almost 80%. Trial registration: NCT01306942, EudraCT 2010-023304-27., The study was financially supported by Bristol-Myers Squibb which also supplied the dasatinib.

Docetaxel is a semi-synthetic taxane with cytotoxic anti-neoplastic activity and, currently used as anticancer agent in several types of cancer. Docetaxel is highly bound to plasma proteins, and this significantly determines its clearance and activity. Therefore, measurement of free docetaxel in plasma is pharmacologically important when pharmacokinetics is investigated. We developed and validated chromatographic methods by ultra-performance liquid chromatography-tandem mass spectrometry to measure total and free docetaxel concentration in human plasma. The final validated methods involved liquid-liquid extraction followed by dryness under nitrogen evaporation. To measure free docetaxel concentration, sample preparation was preceded by ultrafiltration. Chromatographic separation was achieved using an Acquity(®) UPLC(®) BEH™ (2.1×100 mm id, 1.7 μm) reverse-phase C18 column at a flow rate of 0.4 mL/min, using isocratic elution mode containing ammonium acetate/formic acid in water/methanol (30:70 v/v) as mobile phase. Docetaxel and its internal standard (paclitaxel) were detected by electrospray ionization mass spectrometry in positive ion multiple reaction monitoring mode using mass-to-charge (m/z) transitions of 808.3→527.0 (quantifier) and 808.3→509.0 (qualifier); and 854.3→569.0 (quantifier) and 854,3→509,0 (qualifier), respectively. The run time per sample was 3.5 min. The limits of quantification were 1,95 and 0.42 μg/L and linearity was observed between 1.95 and 1000 and 0.42-100 μg/L for total and free docetaxel, respectively. Coefficients of variation and absolute relative biases were less than 13.8% and 10.0%. Recovery values were greater than 79.4%. Evaluation of the matrix effect showed ion suppression and no carry-over was observed. The validated methods could be useful for both therapeutic drug monitoring and pharmacokinetic studies. They could be applied to daily clinical laboratory practice to measure the concentration of total and free docetaxel in plasma.

Prostate cancer (PCa) is the second most common cancer of men and is typically slow-growing and asymptomatic. The use of blood PSA as a screening method has greatly improved PCa diagnosis, but high levels of false positives has raised much interest in alternative biomarkers. We used next-generation sequencing (NGS) to elucidate the urinary transcriptome of whole urine collected from high-stage and low-stage PCa patients as well as from patients with the confounding diagnosis of benign hyperplasia (BPH). We identified and validated five differentially expressed protein-coding genes (FTH1 BRPF1, OSBP, PHC3, and UACA) in an independent validation cohort of small-volume (1 mL) centrifuged urine (n = 94) and non-centrifuged urine (n = 84) by droplet digital (dd)PCR. These biomarkers were able to discriminate between BPH and PCa patients and healthy controls using either centrifuged or non-centrifuged whole urine samples, suggesting that the urinary transcriptome is a valuable source of non-invasive biomarkers for PCa that warrants further investigation.

Background Interstitial lung disease (ILD) associated with Rheumatoid Arthritis (RA) has a poor prognosis. Treatments such as anti-TNF, have been implicated in the exacerbation of an ILD. Objectives Our objective is to evaluate and compare the evolution of ILD in patients with RA treated with Abatacept (ABA), Rituximab (RTX) and Tocilizumab (TCZ) after 1 year of treatment. Methods Retrospective multicentre study of patients with ILD and AR treated with ABA, RTX and TCZ at standard doses. The ILD was diagnosed by CT. The efficacy was evaluated whith the following measures: i) Dyspnea by modified scale of the Medical Research Council (mMRC); considering variations of 1 point. ii) Respiratory function tests; considering variations in FVC and DLCO ≥10%. iii) Imaging test (CT). Results We included 118 (72 women/46 men) patients, mean age of 62.27±10.55 years. The ILD had a median evolution of 12 12–37 months. The RA was ACPA+in 102 cases (86.4%). At diagnosis, the mean DLCO onset of biological treatment was 65.63±19.38. Table 1 shows the characteristics by subgroups. The Figure expresses the evolution in the cases available at 12 months. There is an improvement in CT in 36.4% of patients with ABA, 28.6% of patients with RTX and only 8.3% of patients with TCZ. Conclusions There seems to be a trend towards a better radiological response in patients treated with RTX and ABA. It would be necessary prospective studies. Disclosure of Interest None declared

Background: The outcome for oestrogen receptor positive (ER+) breast cancer patients has improved greatly in recent years largely due to targeted therapy. However, the presence of involved multiple synchronous lymph nodes remains associated with a poor outcome. Consequently, these patients would benefit from the identification of new prognostic biomarkers and therapeutic targets. The expression of G-protein-coupled receptor kinase-interacting protein 1 (GIT1) has recently been shown to be an indicator of advanced stage breast cancer. Therefore, we investigated its expression and prognostic value of GIT1 in a cohort of 140 ER+ breast cancer with synchronous lymph node involvement. Methods: Immunohistochemistry was employed to assess GIT1 expression in a tissue microarray (TMA) containing duplicate non-adjacent cores with matched primary tumour and lymph node tissue (n=140). GIT1 expression in tumour cells was scored and statistical correlation analyses were carried out. Results: The results revealed a sub-group of patients that displayed discordant expression of GIT1 between the primary tumour and the lymph nodes (i.e. spatial intratumoural heterogeneity). We observed that loss of GIT1 expression in the tumour cells of the metastasis was associated with a shorter time to recurrence, poorer overall survival, and a shorter median survival time. Moreover, multivariate analysis demonstrated that GIT1 expression was an independent prognostic indicator. Conclusions: GIT1 expression enabled the identification of a sub-class of ER+ patients with lymph node metastasis that have a particularly poor prognostic outcome. We propose that this biomarker could be used to further stratify ER+ breast cancer patients with synchronous lymph node involvement and therefore facilitate adjuvant therapy decision making.

The fatty acid (FA) composition of red blood cell (RBC) membrane phospholipids of cancer patients can reflect tumor status, dietary intakes, and cancer type or therapy. However, the characteristic membrane profiles have so far not yet defined as a potential biomarker to monitor disease evolution. The present work provides the first evidence of cancer metabolic signatures affecting cell membranes that are independent of nutritional habits. From the Oncology Outpatient Unit of the Onkologikoa hospital, two groups of cancer patients (n = 54) and healthy controls (n = 37) were recruited, and mature RBCs membrane phospholipids were analyzed for FA profiling (GC-MS). Dietary habits were evaluated using a validated food frequency questionnaire. The adjusted Analysis of Covariance Test (ANCOVA) model revealed cancer patients to have a lower relative percentage of saturated fatty acids (SFA) (C16:0 (5.7%), C18:0 (15.9%)), and higher monounsaturated fatty acids (MUFA) (9c-C18:1 (12.9%) and 11c-C18:1 (54.5%)), compared to controls. In line with this, we observe that the desaturase enzymatic index (delta-9 desaturase (&Delta, 9D), +28.3%) and the membrane saturation index (SI = SFA/MUFA, &minus, 27.3%) were similarly modulated. Polyunsaturated fatty acids (PUFA) families showed an increase of n-6 C18:2 and C20:3 (15.7% and 22.2% respectively), with no differences in n-6 C20:4 and n-3 PUFA (docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)). Importantly, these changes were found independent of foods and fat intakes from the diet. The membrane lipid profile in RBC was useful to ascertain the presence of two main metabolic signatures of increased desaturation activity and omega-6 in cancer patients, statistically independent from dietary habits.

Taste and smell changes are common side effects in cancer patients undergoing chemotherapy treatments (CT). This can lead to a reduced food enjoyment and an inadequate nutrient intake with a high impact on nutritional status and quality of life. The aim of this study was to evaluate the self-reported chemosensory alterations of patients undergoing chemotherapy according to CT type. An observational study was conducted with 151 patients undergoing CT at Oncology Outpatient Unit from Onkologikoa Foundation. An interviewer-assisted questionnaire was designed to investigate chemosensory changes in patients undergoing CT. Seventy-six percent patients reported taste disorders and 45% smell changes. Xerostomia is the most frequent symptom reported by patients receiving chemotherapy in our study (63.6%), and it is strongly associated to bad taste in mouth (OR = 5.96; CI = 2.37–14.94; p value = 0.000) and taste loss (OR = 5.96; CI = 2.37–14.94; p value = 0.000). Anthracyclines, paclitaxel, carboplatin, and docetaxel were the CT agents producing the highest taste disturbance rates. Cisplatin and 5-Fluorouracil are the CT resulting in the lowest complaints. Logistic regression revealed statistically significant associations between taste loss and carboplatin and docetaxel (OR = 3.50; CI = 1.12–10.90; p value = 0.031) and cold hypersensitivity and oxaliplatin (OR = 12.14; CI = 4.18–35.25; p value = 0.000). Not only platin-based CT such as carboplatin produced dysgeusia, but also anthracyclines and paclitaxel treatments. The better knowledge of taste and smell alterations according to CT type may provide valuable information for the design of new strategies to tackle CT side effects. It is important to take into account taste and smell dysfunctions and other alterations such as xerostomia together.

Guideline-based clinical decision support systems (CDSSs) are expected to improve the quality of care by providing best evidence-based recommendations. However, because clinical practice guidelines (CPGs) may be incomplete and often lag behind the publication time of very last scientific results, CDSSs may not provide up-to-date treatments. It happens that clinical decisions made for specific patients do not comply with CDSS recommendations, whereas they comply with the state of the art. They may also be non-compliant because they rely on some implicit knowledge not covered by CPGs. We propose to capitalize the clinical know-how built from such non-compliant decisions and allow physicians to use it in future similar cases by the development of a decisional event structure that allows the modelling, storage, processing, and reuse of all the information related to a decision-making process. This structure allows the analysis of non-compliant decisions, which generates new experience-based rules. These new rules augment the knowledge embedded in CPGs supporting clinician decision for specific patients poorly covered by CPGs. This work is applied to the management of breast cancer within the EU Horizon 2020 project DESIREE.

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings.METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants.FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events.FUNDING: Wyeth, Pfizer, and Puma Biotechnology.

Altres ajuts: FIS-PI14-00336 FN14 has been implicated in many intracellular signaling pathways, and GRP94 is a well-known endoplasmic reticulum protein regulated by glucose. Recently, both have been associated with metastasis progression in breast cancer patients. We studied the usefulness of FN14 and GRP94 expression to stratify breast cancer patients according their risk of brain metastasis (BrM) progression. We analyzed FN14 and GRP94 by immunohistochemistry in a retrospective multicenter study using tissue microarrays from 208 patients with breast carcinomas, of whom 52 had developed BrM. Clinical and pathological characteristics and biomarkers expression in Luminal and non-Luminal patients were analyzed using a multivariate logistic regression model adjusted for covariates, and brain metastasis-free survival (BrMFS) was estimated using the Kaplan-Meier method and the Cox proportional hazards model. FN14 expression was associated with BrM progression mainly in Luminal breast cancer patients with a sensitivity (53.85%) and specificity (89.60%) similar to Her2 expression (46.15 and 89.84%, respectively). Moreover, the likelihood to develop BrM in FN14-positive Luminal carcinomas increased 36.70-fold (3.65-368.25, p = 0.002). Furthermore, the worst prognostic factor for BrMFS in patients with Luminal carcinomas was FN14 overexpression (HR = 8.25; 95% CI: 2.77-24.61; p = 0.00015). In these patients, GRP94 overexpression also increased the risk of BrM (HR = 3.58; 95% CI: 0.98-13.11; p = 0.054-Wald test). Therefore, FN14 expression in Luminal breast carcinomas is a predictive/prognostic biomarker of BrM, which combined with GRP94 predicts BrM progression in non-Luminal tumors 4.04-fold (1.19-8.22, p = 0.025), suggesting that both biomarkers are useful to stratify BrM risk at early diagnosis. We propose a new follow-up protocol for the early prevention of clinical BrM of breast cancer patients with BrM risk.

// Alberto Ocana 1 , Marta Gil-Martin 2 , Miguel Martin 3 , Federico Rojo 4 , Silvia Antolin 5 , Angel Guerrero 6 , Jose Manuel Trigo 7 , Montse Munoz 8 , Atanasio Pandiella 9 , Nuria Gonzalo Diego 10 , Susana Bezares 11 , Rosalia Caballero 12 , Eva Carrasco 11 and Ander Urruticoechea 13 1 Department of Medical Oncology, Complejo Hospitalario Universitario de Albacete, Albacete, Spain 2 Department of Medical Oncology, Institut Catala d’Oncologia-IDIBELL, L’Hospitalet, Barcelona, Spain 3 Department of Medical Oncology, Instituto de Investigacion Sanitaria Gregorio Maranon, Universidad Complutense, Madrid, Spain 4 Fundacion Jimenez Diaz, Madrid, Spain 5 Department of Medical Oncology, Complejo Hospitalario Universitario A Coruna, La Coruna, Spain 6 Department of Medical Oncology, Instituto Valenciano de Oncologia, Valencia, Spain 7 Department of Medical Oncology, Hospital Clinico Universitario Virgen de la Victoria, Malaga, Spain 8 Department of Medical Oncology, Hospital Clinic i Provincial de Barcelona, Barcelona, Spain 9 Centro de Investigacion del Cancer and CIBERONC, CSIC-Universidad de Salamanca, Salamanca, Spain 10 Pharmacokinetics Laboratory, Farmacia ICO Metropolitana, IDIBELL, Instituto Catalan de Oncologia, Hospital Duran i Reynals, Barcelona, Spain 11 Scientific Department, GEICAM Spanish Breast Cancer Group, Spain 12 Translational Department, GEICAM Spanish Breast Cancer Group, Spain 13 Department of Medical Oncology, Fundacion Onkologikoa, Donostia, Gipuzkoa, Spain Correspondence to: Alberto Ocana, email: // Keywords : HER2 positive breast cancer, dasatinib, SRC kinase, trastuzumab resistance, metastatic breast cancer Received : March 04, 2017 Accepted : April 04, 2017 Published : April 14, 2017 Abstract The anti-HER2 antibody trastuzumab have shown clinical activity in combination with chemotherapy in different breast cancer settings. However, most of patients treated with this antibody progress after a period of treatment. Activation of the kinase SRC has been linked with resistance to trastuzumab in several preclinical studies. We designed a phase I clinical study to explore the activity of weekly trastuzumab (2 mg/kg) plus paclitaxel (80 mg/m 2 ) in combination with the anti-SRC kinase inhibitor Dasatinib in the first line treatment of HER2 metastatic breast cancer. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D); secondary objectives included efficacy, objective response rate (ORR), pharmacokinetics and pharmacodynamics. A “3+3” design guided dose escalation with two oral dose levels of dasatinib: 100mg (DL1) and 140 mg (DL2). 10 patients were included in the phase I part. Dasatinib 100 mg q.d. was established as the recommended RP2D. The median number of administered cycles was 12 (range, 1 to 18). Grade 3 treatment-related AEs at DL1 were diarrhea ( n = 2), hyponatremia ( n = 1), fatigue ( n = 1), and AST/ALT elevation ( n = 1). A significant reduction in p-SRC expression on epidermal keratinocytes on sequential skin biopsies was observed. In conclusion, we describe the feasibility of the combination of dasatinib, trastuzumab and paclitaxel, and its effect on proteins involved in trastuzumab resistance. The phase II part of this study is currently evaluating efficacy.

Introduction: Previous small-molecule antiangiogenics have compromised chemotherapy dose intensity in breast cancer. We present a phase I trial of a novel selective agent, nintedanib, plus standard chemotherapy in early breast cancer. Methods: Her-2-negative breast cancer patients with tumours larger than 2 cm were eligible for dose-escalation trial (classic 3+3 method). Results: The recommended phase II dose (RP2D) was 150 mg BID of nintedanib combined with standard dose of weekly paclitaxel followed by adriamycin plus cyclophosphamide. The dose-limiting toxicity was transaminase elevation. At the RP2D, the dose intensity was ∼100%. The pathologic complete response was 50%. Conclusions: The combination allows the delivery of full-dose intensity, while efficacy seems promising.

Resumen Objetivos La importancia de obtener margenes libres en la cirugia conservadora de mama es conocida. Sin embargo, no existe uniformidad a la hora de plantear una reescision, por ello desde el Grupo de Estudios Senologicos decidimos conocer la realidad de nuestro pais mediante una encuesta Material y metodo Se elaboro una encuesta en linea que constaba de 28 items distribuidos en 4 apartados: generalidades, informacion y decision peroperatoria, informacion y decision postoperatoria, y otros. Se envio a 87 centros de los que contestaron 55 (63,2%). Resultados En el 60% de los casos los margenes se examinan de forma intraoperatoria siempre y en el 22% de forma ocasional. El 58% entiende por margen proximo el margen inferior a 1 mm. Cuando la informacion de margen afecto, focalmente afecto o proximo a tumor es intraoperatoria, en la mayoria de los centros se opta por la ampliacion quirurgica. Si la informacion es postoperatoria, en caso de margen afecto o focalmente afecto se realiza una reescision en una amplio porcentaje de pacientes (70-100%) y si son proximos solo en el 18-29%. En caso de afectacion de margenes y no reescision quirurgica en el 50% de los casos se aumenta la dosis de radiacion. Conclusion Actualmente en nuestro medio, ante la afectacion de los margenes quirurgicos la decision mayoritaria es la reescision. Sin embargo, existe una variabilidad no despreciable en esta decision cuando la informacion es de proximidad del margen quirurgico.

BACKGROUND: The combination of a CDK4/6 inhibitor (palbociclib, abemaciclib, or ribociclib) with an aromatase inhibitor (AI) significantly reduces Ki67 compared to single-agent AI in the neoadjuvant setting, but the rates of pathological complete response (pCR) or residual cancer burden (RCB) 0-I remain modest. Despite this inadequate pathological downstaging, to date, there is no data about the efficacy of this treatment in terms of molecular downstaging detected by a more refined genomic signature than Ki67, such as the Oncotype DX Breast Recurrence Score® (RS) test. The aim of this trial is to validate the ability of neoadjuvant palbociclib plus letrozole to modify two initial intermediate or high RS tumor cohorts. TRIAL DESIGN: This is an international, multicenter, open-label, non-comparative, phase II trial. Main selection criteria include: (1) Pre- or post-menopausal women with treatment-naïve, centrally assessed, HR-positive/HER2-negative, Ki67 ≥ 20%, and stage II-IIIB breast cancer; (2) Pre-treatment RS result ≥ 18; (3) Patients agree to collect tissue samples at screening, at Cycle 1 Day 14 of treatment, and at surgery. Patients will be allocated, according to the pre-treatment RS result, either to Cohort A (RS 18-25) or Cohort B (RS 26-100) and will receive treatment with palbociclib (125 mg QD, 3/1 schedule) in combination with letrozole (2.5 mg QD, every 28-day cycle), ± LHRH analogs if pre-menopausal status, for 24 weeks. Definitive breast surgery will be performed within 7 days after completion of 6 treatment cycles. The primary objective of the study is to explore the ability of palbociclib in combination with letrozole to induce global molecular changes, measured by either the post-treatment RS result at surgery, or pCR. Secondary objectives include: (1) Concordance rate among post-treatment RS result and RCB, Ki67, and preoperative endocrine prognostic index (PEPI) score; (2) Overall response rate; (3) Safety-related outcome as per Common Terminology Criteria for Adverse Events v. 5.0. Patients will be accrued in a Simon’s two-stage design trial: optimal design in Cohort A and minimax design in Cohort B. With a unilateral type one error (alpha) set at 0.025 and a 0.8 power (type two error beta = 0.2), the required number of evaluable patients are 28. Considering a drop-out rate no lower than 10%, a sample size of 33 patients in each cohort will be needed. First Patient First Visit: Expected on April 2019. Citation Format: Antonio Llombart Cussac, José Pérez-García, Ángel Guerrero, Begoña Bermejo, Miguel Gil, Vicente Carañana, Serafín Morales, Juan de la Haba, María Fernández, Emilio Alba, Ander Urruticoechea, Lourdes Calvo, Mireia Margeli, Antonio Antón, Manuel Ruíz Borrego, Joan Albanell, Pedro Sánchez Rovira, Meritxell Bellet, Sofia Braga, Passos Coelho, Miguel Abreu, Javier Cortés. Neoadjuvant letrozole and palbociclib in stage II-IIIB HR[+]/HER2[-] breast cancer with Oncotype DX Recurrence Score® (RS) 18-25 or 26-100. Analysis of RS changes at surgery (DxCARTES trial) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT219.

Background: The PI3K/Akt/mTOR pathway is the most frequently activated signaling pathway in breast cancer (BC). Activation of this pathway promotes tumor growth and progression, and resistance to anticancer therapies, including paclitaxel (PTX). BEZ235 is an oral, ATP-competitive inhibitor that targets class l PI3K and downstream effectors mTORC1/2. BEZ235 has shown antiproliferative, proapoptotic, and antiangiogenic activity in multiple preclinical cancer models. In a Ph I study, single-agent BEZ235 given twice daily (BID) showed preliminary signs of clinical activity. Methods: This was a multicenter, open-label Ph Ib/II study of daily, oral BEZ235 given BID in combination with weekly (QW) intravenous PTX in women with HER2-, metastatic or locally advanced BC (NCT01495247). For the Ph Ib part, the primary objective was to determine the maximum tolerated dose (MTD)/recommended Ph II dose (RP2D) of BEZ235 in combination with PTX based on dose-limiting toxicities (DLTs) using a 5-parameter adaptive Bayesian logistic regression model with overdose control. MTD was defined as the highest dose not causing medically unacceptable DLTs in >35% of pts during Cycle 1 (28 days). Secondary objectives included safety, preliminary activity, and PK. Safety was monitored by physical exams, vital signs, laboratory tests, weight, and cardiac health. AEs were assessed continuously by CTCAE v4.03. Tumor evaluations were performed at screening and every 8 wks after starting treatment, and assessed locally by RECIST v1.1. Results: As of April 12, 2013, 18 pts (mean age: 50 yr; 67% ≥4 prior lines of antineoplastic therapy) had been enrolled into Ph Ib. 13 pts received BEZ235 200 mg BID + PTX 80 mg/m2 QW. The dose level was then reduced to BEZ235 100 mg BID + PTX 80 mg/m2 QW (n = 5). Of 17 evaluable pts (12 at the 200-mg BID dose; 5 at the 100-mg BID dose), 6 (35%) developed ≥1 DLTs (5 [42%] at the 200-mg BID dose; 1 [20%] at the 100-mg BID dose): neutropenia (n = 3 [1 at the 100-mg BID dose]), stomatitis (n = 3), nausea (n = 2), and vomiting (n = 1). Of 18 pts, 12 have discontinued (6 due to disease progression; 4 AEs; 1 physician decision; 1 pt/guardian decision). Median duration of exposure to BEZ235 and PTX was 76 days each. The most common suspected study drug-related AEs included asthenia (78%), nausea (72%), neutropenia (72%), diarrhea (67%), stomatitis (61%), and decreased appetite (56%). Among 13 pts receiving BEZ235 200 mg BID, 2 (15%) achieved a PR, 4 (31%) had SD, and 4 (31%) had PD; all 5 pts receiving BEZ235 100 mg BID had SD. PK results showed large interpatient variability at both dose levels. Analysis of pAKT and p4EBP1 was performed on peripheral blood mononuclear cells collected from pts before treatment and 4 h following treatment (Cmax). PK/PD analysis did not provide evidence of a strong and consistent correlation between BEZ235 plasma concentrations and pAKT inhibition. Conclusions: The MTD/RP2D of BEZ235 in combination with PTX in pts with locally advanced or metastatic HER2- BC was not reached. Based on the observed overall safety profile, efficacy, variable PK, and PD data from the Ph Ib part of this study, further enrollment has stopped. The Ph II part of the study will not be conducted. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-22.

The aqueous solubility of lapatinib declines significantly at pH >4, suggesting that its bioavailability might be lowered by acid-reducing drugs. A study was therefore conducted to assess the effects of esomeprazole on lapatinib pharmacokinetics (PK). Women with metastatic human epidermal growth factor receptor 2 positive (HER2(+) ) breast cancer were enrolled. Patients received 1,250 mg lapatinib once daily (QD) in the morning on Days 1-7 (Period 1) and Days 8-14 (Period 2) with 40 mg esomeprazole QD at bedtime 3 hours after dinner on Days 8-14. Lapatinib PK sampling occurred during the 24-hour steady-state dosing intervals on Day 7 (lapatinib alone) and Day 14 (lapatinib with esomeprazole). Esomeprazole treatment resulted in decreased lapatinib bioavailability (mean 26%, range 6-49%) that was inversely associated with patient age as a significant covariate.