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Background Benefit derived from adjuvant chemotherapy (CT) is doubtful in a high percentage of patients (pt) with hormone-receptor–positive HER2 negative early breast cancer. The 21-gene recurrence-score (RS) assay Oncotype DX, provide prognostic and predictive information. Results of the TAYLORx study have confirmed that most of patients with negative node status and RS > 25 can avoid CT without increasing their risk of relapse. However, pt 20 showed benefit with CT. Methods Aim: To analyse the impact of age using RS test to change the indication of adjuvant CT and the relationship between different clinical pathological factors and the RS value. We analysed 240 cases out of 251 RS test performed in the 3 ICO Centers during 2017-2018. We compared the adjuvant treatment initially planned according to institutional protocol with the treatment given after RS in the total cohort and in pt Results CT was indicated in all pt before knowing the RS results. Only 46 pt (19%) received CT after RS results. 14 out of 88 pt 25 ( 25 in a multivariate analysis. Table . 209P Age median (range) 53 (19-76) Tumor size median 15 mm Histological grade G1 23% G2 69.7% G3 4.4% Progesterone receptor ≤20% 21% >20% 78% Ki67 median (p25-75) 20 (13,28) ≤14 27% 14-25 41% >25% 31% Nodal status pN0 57% pN1mic 15% pN1a 27% Conclusions 82% of pt of our series could avoid CT, however this proportion change after TAYLORx results in younger patients. Today 75% of these pt would had avoided CT. Ki67 > 25% and Progesterone Receptor ≤20% were the only pathological factors associated with an increased risk of RS > 25. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background: The minor allele (C) of the single-nucleotide polymorphism (SNP) rs11212617, located near the ataxia telangiectasia mutated (ATM) gene, has been associated with an increased likelihood of treatment success with metformin in type 2 diabetes. We herein investigated whether the same SNP would predict clinical response to neoadjuvant metformin in women with early breast cancer (BC). Methods: DNA was collected from 79 patients included in the intention-to-treat population of the METTEN study, a phase 2 clinical trial of HER2-positive BC patients randomized to receive either metformin combined with anthracycline/taxane-based chemotherapy and trastuzumab or equivalent regimen without metformin, before surgery. SNP rs11212617 genotyping was assessed using allelic discrimination by quantitative polymerase chain reaction. Results: Logistic regression analyses revealed a significant relationship between the rs11212617 genotype and the ability of treatment arms to achieve a pathological complete response (pCR) in patients (odds ratio [OR]genotype×arm = 10.33, 95% confidence interval [CI]: 1.29–82.89, p = 0.028). In the metformin-containing arm, patients bearing the rs11212617 C allele had a significantly higher probability of pCR (ORA/C,C/C = 7.94, 95%CI: 1.60–39.42, p = 0.011). Conversely, no association was found between rs11212617 and clinical response in the reference arm (ORA/C,C/C = 0.77, 95%CI: 0.20–2.92, p = 0.700). After controlling for tumor size and hormone receptor status, the rs11212617 C allele remained a significant predictor of pCR solely in the metformin-containing arm. Conclusions: If reproducible, the rs11212617 C allele might warrant consideration as a predictive clinical biomarker to inform the personalized use of metformin in BC patients. Trial Registration: EU Clinical Trials Register, EudraCT number 2011-000490-30. Registered 28 February 2011, https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-000490-30/ES.

Objectives: The key objectives of CONTESSA are to evaluate the efficacy and safety of tesetaxel plus a reduced dose of capecitabine as an all-oral regimen versus capecitabine alone in patients with HER2-, HR+ MBC previously treated with a taxane. Rationale: Tesetaxel is a novel, oral taxane with several properties that make it unique, including: oral administration with a low pill burden; a long (8-day) terminal plasma half-life in humans, enabling infrequent, once-every-3 weeks (Q3W) dosing; no observed hypersensitivity reactions; and significant activity against chemotherapy-resistant breast cancer cell lines. More than 1,000 patients have been treated with tesetaxel in clinical studies. Tesetaxel had encouraging monotherapy activity in a Phase 2 study in 38 patients with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45% and median progression-free survival (PFS) of 5.4 months (Seidman et al, 2018 ASCO Annual Meeting). Methodology: CONTESSA is a multinational, multicenter, randomized (1:1), Phase 3 registration study comparing tesetaxel (27 mg/m2 on Day 1 of a 21-day cycle) plus a reduced dose of capecitabine (1,650 mg/m2/day on Days 1-14 of a 21-day cycle) to the approved dose of capecitabine alone (2,500 mg/m2/day on Days 1-14 of a 21-day cycle) in patients with HER2-, HR+ MBC who have received no more than one chemotherapy regimen for advanced disease and have received a taxane in the (neo)adjuvant setting. There was no restriction on the disease-free interval following taxane therapy. The primary endpoint is PFS assessed by an Independent Radiologic Review Committee (IRC). CONTESSA was designed with 90% power to detect a 2.5-month improvement in median PFS (HR=0.71). Secondary endpoints are overall survival (OS), ORR and disease control rate. Results: CONTESSA, which enrolled 685 patients, met the primary endpoint of improved PFS as assessed by the IRC. Median PFS was 9.8 months for tesetaxel plus a reduced dose of capecitabine versus 6.9 months for capecitabine alone, an improvement of 2.9 months [HR=0.716 (95% CI: 0.573-0.895); p=0.003]. ORR was 57% for tesetaxel plus a reduced dose of capecitabine versus 41% for capecitabine alone (p=0.0002). OS data are immature. Tesetaxel plus capecitabine was associated with a manageable side effect profile consistent with previous clinical studies. Grade ≥3 treatment-emergent adverse events (TEAEs) that occurred in ≥5% of patients (tesetaxel plus capecitabine vs. capecitabine alone) were: neutropenia (71.2% vs. 8.3%); diarrhea (13.4% vs. 8.9%); hand-foot syndrome (6.8% vs. 12.2%); febrile neutropenia (12.8% vs. 1.2%); fatigue (8.6% vs. 4.5%); hypokalemia (8.6% vs. 2.7%); leukopenia (10.1% vs. 0.9%); and anemia (8.0% vs. 2.1%). TEAEs resulting in treatment discontinuation in ≥1% of patients (tesetaxel plus capecitabine vs. capecitabine alone) were: neutropenia or febrile neutropenia (4.2% vs. 1.5%); neuropathy (3.6% vs. 0.3%); diarrhea (0.9% vs. 1.5%); and hand-foot syndrome (0.6% vs. 2.1%). Treatment discontinuation due to any adverse event occurred in 23.1% of patients treated with tesetaxel plus capecitabine versus 11.9% of patients treated with capecitabine alone. Grade 2 alopecia occurred in 8.0% of patients treated with tesetaxel plus capecitabine versus 0.3% of patients treated with capecitabine alone. Grade ≥3 neuropathy occurred in 5.9% of patients treated with tesetaxel plus capecitabine versus 0.9% of patients treated with capecitabine alone. Conclusion: An all-oral regimen of tesetaxel plus a reduced dose of capecitabine significantly improved PFS versus capecitabine alone. Neutropenia was the most frequent Grade ≥3 TEAE. Rates of clinically significant alopecia and neuropathy were low. Citation Format: Joyce O'Shaughnessy, Lee Schwartzberg, Martine Piccart, Hope S. Rugo, Denise A Yardley, Javier Cortes, Michael Untch, Nadia Harbeck, Gail S. Wright, Igor Bondarenko, John Glaspy, Zbigniew Nowecki, Fadi Kayali, Arlene Chan, Christelle Levy, Mei-Ching Liu, Sung-Bae Kim, Julie Lemieux, Alexey Manikhas, Sara Tolaney, Elaine Lim, Andrea Gombos, Agostina Stradella, Mark Pegram, Peter Fasching, Laszlo Mangel, Vladimir Semiglazov, Veronique Dieras, Luca Gianni, Michael A Danso, Jeff Vacirca, Stew Kroll, Joseph O'Connell, Kevin Tang, Thomas Wei, Andrew Seidman. Results from CONTESSA: A phase 3 study of tesetaxel plus a reduced dose of capecitabine versus capecitabine alone in patients with HER2-, hormone receptor + (HR+) metastatic breast cancer (MBC) who have previously received a taxane [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 GS4-01.

Introduction: Benefit derived from adjuvant chemotherapy (CT) is doubtful in a high percentage of patients with early breast cancer. The 70-genes platform MMP improves prognostic classification and has been proven useful when it comes to individualizing treatment options. At our institution we use this test to try to avoid overtreatment in those patients in which CT benefit is unclear. We defined some criteria in order to discriminate better which patients would benefit most from the MMP assessment as well as to identify a group of subjects where the test would be more cost-effective. These criteria were: age between 35-70 years, tumor size from 1 to 3 cm, histological grade 2, absence of macrometastatic disease in axillary nodes, hormone receptors positive, HER2 negative and Ki67 between 11-25%. Objective: To analyze the impact of using MMP to help selecting adjuvant treatment, both in clinical and economical aspects. Material and Methods: Since August 2012 to January 2015, MMP genetic signature was performed in 129 early tumors samples. Most cases met the criteria explained above. Some that did not were also included by decision of the institution multidisciplinary committee when the individual characteristics of the cases where taken into account. We compiled the adjuvant treatment initially planned according to our institution protocol and usual clinical practice and compared it with the actual treatment given after the results of the test were known. We calculated the direct economic costs of chemotherapy and of the diagnostic test. Results: The clinical characteristics of the patients and the adjuvant therapy they received are shown in Table 1. Patients Characteristicsn=129 Age, median (range)54.5 (20-76)Histology Infiltrating ductal carcinoma115 (89%)Infiltrating lobular carcinoma14 (11%)pT (mm) Median (range)15 (8-60)Mean (range)18.55 (8-60)pN pN087 (67.4%)pN1mic30 (23.2%)pN17 (5.4%)pN21 (0.8%)Histological grade I24 (18.8%)II100 (78.1%)III4 (3.1%)Hormone receptors ER 50-100%129 (100%)PR 20%108 (83.7%)Ki 67 20%54 (42.2%)Median (range)20 (1-35)Mean (range)19.95 (1-35)Her 2 negative129 (100%)Adjuvant treatment FEC-paclitaxel + Hormonotherapy18TAC + Hormonotherapy27Hormonotherapy84 119 Patients (92.2%) would have received adjuvant CT without MMP risk determination. After the results only 45 patients (34.9%) received it. The cost of the genetic study was 306.725€. Direct costs savings estimated from the reduction in CT treatment were 494.771,48 €. Conclusion: The use of the MMP test in a selected group of patients reduced the administration of adjuvant CT in a 57.3%. This represented a saving of 188.046,48€. Citation Format: Rullan AJ, Pernas S, Margelí M, Joan D, Quiroga V, Stradella A, Petit A, Germà JR, Calle C, Falo C, Ponton JL, Gil-Gil M. Use of Mammaprint© (MMP) genetic signature in early breast cancer patients. Economic analisys of a 129 patient cohort treated in three Spanish hospitals. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-11-04.

TPS1111 Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. T is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and once every 3 week (Q3W) dosing; no observed hypersensitivity reactions; preclinical evidence of central nervous system (CNS) penetration; and improved activity against chemotherapy-resistant tumors. More than 600 pts have been treated with T in clinical studies. T had robust monotherapy activity in a P2 study in 38 pts with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45%. Methods: CONTESSA TRIO is a 2-cohort, multinational, multicenter, P2 study. In Cohort 1, 90 pts (potential expansion to up to 150 pts) with metastatic TNBC who have not received prior chemotherapy for advanced disease will be randomized 1:1:1 to receive T at 27 mg/m2 Q3W plus either: (1) nivolumab at 360 mg Q3W; (2) pembrolizumab at 200 mg Q3W; or (3) atezolizumab at 1,200 mg Q3W. Nivolumab and pembrolizumab (PD-1 inhibitors) and atezolizumab (a PD-L1 inhibitor) are approved for the treatment of multiple types of cancer; atezolizumab, in combination with nab-paclitaxel, was recently approved in the US for the treatment of metastatic TNBC. The dual primary endpoints for Cohort 1 are ORR and progression-free survival (PFS). A sample size of 30 pts in each PD-(L)1 inhibitor treatment group has approximately 70% power to detect an ORR difference of ≥ 35% between the treatment group with the highest ORR and the treatment group with the lowest ORR. Secondary endpoints include duration of response (DoR) and overall survival (OS). Efficacy results for each of the 3 PD-(L)1 inhibitor combinations will be assessed for correlation with the results of each of the 3 approved PD-L1 diagnostic assays. CONTESSA TRIO is the first randomized clinical study to compare 3 approved PD-(L)1 inhibitors. In Cohort 2, 40 elderly pts (potential expansion to up to 60 pts) with HER2- MBC who have not received prior chemotherapy for advanced disease will receive T monotherapy at 27 mg/m2 Q3W. The primary endpoint for Cohort 2 is ORR. A sample size of 40 will allow the ORR to be estimated with a maximum standard error of < 8%. Secondary endpoints include PFS, DoR and OS. Pts with CNS metastases are eligible for both cohorts. The study was initiated in March 2019. Clinical trial information: NCT03952325 .

503 Background: Dual trastuzumab plus pertuzumab (HP) has shown promising pathologic complete response (pCR) rates in HER2[+] EBC although lower to CT regimens. Identification of new markers of sensitivity to HP could help to de-escalate CT. PHERGain assessed early metabolic response by F-PET to neoadjuvant HP and the opportunity of CT de-escalation with a response-adapted strategy in patients (pts) with HER2[+] EBC. Methods: PHERGain randomized (1:4 ratio) centrally-confirmed HER2[+] stage I-III EBC pts to receive either docetaxel (T), carboplatin (C), and HP (cohort A) or HP ± endocrine therapy (ET) (cohort B). Randomization was stratified by hormone receptor (HR) status. Pts with subclinical metastases by F-PET were included in a different cohort (cohort C). Centrally-reviewed F-PET was performed prior to randomization and after 2 cycles of TX (cohorts A/B). Cohort A pts completed a total of 6 cycles regardless of F-PET results. Cohort B/PET-responder (RX) pts continued with HP ± ET for 6 cycles, while PET-non-RX pts were switched to receive 6 cycles of TCHP. After surgery, cohort B/PET-RX pts who did not achieve a pCR received 6 cycles of TCHP and all pts from cohorts A/B completed 18 cycles of HP. Cohort C pts received 6 cycles of TCHP. Co-primary endpoints were breast/axilla pCR rate (ypT0/isN0) among cohort B/PET-RX pts and 3-year invasive disease-free survival (iDFS) in pts allocated to cohort B. Results: A total of 376 pts were included (71 pts in cohort A, 285 pts in cohort B, and 20 pts in cohort C). In cohort B, median age was 50 years, 49.2% had node-positive disease, and 67.4% had HR+ tumors. pCR in cohort A was achieved in 41 pts (57.7%, 95% CI 47.4-69.4%) and it was observed in 101 pts included in cohort B (35.4%, 95% CI 29.9-41.3%). Among cohort B pts, 227 (79.6%) were PET-RX; 86 of them (37.9%, 95% CI 31.6-44.5%) obtained a pCR. Among PET-non-RX pts, 15 (25.9%, 95% CI 15.3-39%) achieved a pCR after adding CT (TCHP). PET-RX pCR by HR status was 44.3% for HR[-] and 35% for HR[+] (p = 0.184). The incidence of commonly reported adverse events (AEs) was higher in pts allocated to cohort A (grade≥3 AEs 58.8 vs 12%; serious AEs 29.4 vs 4.6%). The rate of pts with a ≥10% global health status decline in cohorts A and B were 40.8 and 23.5%, respectively. Conclusions: F-PET identify pts with HER2[+] EBC who are more likely to benefit from CT-free dual HER2-blockade with HP. Follow-up is ongoing for iDFS endpoint. Depending on the results of this second co-primary endpoint, this strategy could select a group of HER2[+] EBC pts who would not need CT. Clinical trial information: NCT03161353 .

Metformina; Ki67; Càncer de mama Metformina; Ki67; Cáncer de mama Metformin; Ki67; Breast cancer The proliferative capacity of residual breast cancer (BC) disease indicates the existence of partial treatment resistance and higher probability of tumor recurrence. We explored the therapeutic potential of adding neoadjuvant metformin as an innovative strategy to decrease the proliferative potential of residual BC cells in patients failing to achieve pathological complete response (pCR) after pre-operative therapy. We performed a prospective analysis involving the intention-to-treat population of the (Metformin and Trastuzumab in Neoadjuvancy) METTEN study, a randomized multicenter phase II trial of women with primary, non-metastatic (human epidermal growth factor receptor 2) HER2-positive BC evaluating the efficacy, tolerability, and safety of oral metformin (850 mg twice-daily) for 24 weeks combined with anthracycline/taxane-based chemotherapy and trastuzumab (arm A) or equivalent regimen without metformin (arm B), before surgery. We centrally evaluated the proliferation marker Ki67 on sequential core biopsies using visual assessment (VA) and an (Food and Drug Administration) FDA-cleared automated digital image analysis (ADIA) algorithm. ADIA-based pre-operative values of high Ki67 (≥20%), but not those from VA, significantly predicted the occurrence of pCR in both arms irrespective of the hormone receptor status (p = 0.024 and 0.120, respectively). Changes in Ki67 in residual tumors of non-pCR patients were significantly higher in the metformin-containing arm (p = 0.025), with half of all patients exhibiting high Ki67 at baseline moving into the low-Ki67 (

Understanding the mechanisms of cancer therapeutic resistance is fundamental to improving cancer care. There is clear benefit from chemotherapy in different breast cancer settings; however, knowledge of the mutations and genes that mediate resistance is incomplete. In this study, by modeling chemoresistance in patient-derived xenografts (PDXs), we show that adaptation to therapy is genetically complex and identify that loss of transcription factor 4 (TCF4; also known as ITF2) is associated with this process. A triple-negative BRCA1-mutated PDX was used to study the genetics of chemoresistance. The PDX was treated in parallel with four chemotherapies for five iterative cycles. Exome sequencing identified few genes with de novo or enriched mutations in common among the different therapies, whereas many common depleted mutations/genes were observed. Analysis of somatic mutations from The Cancer Genome Atlas (TCGA) supported the prognostic relevance of the identified genes. A mutation in TCF4 was found de novo in all treatments, and analysis of drug sensitivity profiles across cancer cell lines supported the link to chemoresistance. Loss of TCF4 conferred chemoresistance in breast cancer cell models, possibly by altering cell cycle regulation. Targeted sequencing in chemoresistant tumors identified an intronic variant of TCF4 that may represent an expression quantitative trait locus associated with relapse outcome in TCGA. Immunohistochemical studies suggest a common loss of nuclear TCF4 expression post-chemotherapy. Together, these results from tumor xenograft modeling depict a link between altered TCF4 expression and breast cancer chemoresistance.

Background Chemotherapy (CT) treatments with robust efficacy that preserve quality of life are needed. Tesetaxel (T) is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and once every 3 week (Q3W) dosing; no observed hypersensitivity reactions; and preclinical evidence of central nervous system (CNS) penetration and improved activity against CT-resistant tumors. More than 600 pts have been treated with T in clinical studies. T had robust monotherapy activity in a phase 2 study in 38 pts with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45%. Trial design CONTESSA TRIO is a 2-cohort, multinational, multicenter, Phase 2 study. In Cohort 1, 90 pts (with potential expansion to up to 150 pts) with metastatic TNBC who have not received prior CT for advanced disease will be randomized 1:1:1 to receive T at 27 mg/m2 Q3W plus either: (1) nivolumab at 360 mg Q3W; (2) pembrolizumab at 200 mg Q3W; or (3) atezolizumab at 1,200 mg Q3W. Nivolumab and pembrolizumab (PD-1 inhibitors) and atezolizumab (a PD-L1 inhibitor) are approved for the treatment of multiple types of cancer; atezolizumab, in combination with nab-paclitaxel, was recently approved in the U.S. for the treatment of metastatic TNBC. The dual primary endpoints for Cohort 1 are ORR and progression-free survival (PFS). Secondary endpoints include duration of response (DoR) and overall survival (OS). Efficacy results for each of the 3 PD-(L)1 inhibitor combinations will be assessed for correlation with the results of each of the 3 approved PD-L1 diagnostic assays. CONTESSA TRIO is the first randomized clinical study to compare 3 approved PD-(L)1 inhibitors. In Cohort 2, 40 elderly pts (with potential expansion to up to 60 pts) with HER2- MBC who have not received prior CT for advanced disease will receive T monotherapy at 27 mg/m2 Q3W. The primary endpoint for Cohort 2 is ORR. Secondary endpoints include PFS, DoR and OS. Pts with CNS metastases are eligible for both cohorts. The Study was initiated in March 2019. Clinical trial identification EudraCT: 2018-004715-41. Legal entity responsible for the study Odonate Therapeutics, Inc. Funding Odonate Therapeutics, Inc. Disclosure S.M. Tolaney: Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Cyclacel; Advisory / Consultancy, Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Odonate Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Nektar Therapeutics; Advisory / Consultancy: Tesaro; Advisory / Consultancy: NanoString Technologies; Advisory / Consultancy: Puma Biotechnology. J.L. Blum: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Medivation; Advisory / Consultancy: Novartis; Research grant / Funding (institution): Bristol-Myers Squibb. A. Chan: Research grant / Funding (institution): Eisai; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Puma Biotechnology; Speaker Bureau / Expert testimony: Prime Oncology; Travel / Accommodation / Expenses: Pierre Fabre. Y. Feng: Research grant / Funding (institution), Full / Part-time employment: Chi Mei Medical Center. S. Kim: Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Sanofi-Genzyme; Research grant / Funding (institution): DongKook Pharmaceutical. M. Liu: Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca. M. Oliveira: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (institution): GSK; Advisory / Consultancy, Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Philips Healthcare; Research grant / Funding (institution): Genentech; Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Boehringer-Ingelheim; Travel / Accommodation / Expenses: Pierre-Fabre; Travel / Accommodation / Expenses: GP Pharma; Travel / Accommodation / Expenses: Grunenthal. M. Pavic: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Celgene; Honoraria (self): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Takeda; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Astellas Pharma; Travel / Accommodation / Expenses: Taiho Pharmaceutical; Travel / Accommodation / Expenses: Bayer. H.S. Rugo: Research grant / Funding (institution), Travel / Accommodation / Expenses, Mandatory publication support: Roche/Genentech; Research grant / Funding (institution), Travel / Accommodation / Expenses, Mandatory publication support: Pfizer; Travel / Accommodation / Expenses: Puma Biotechnology; Travel / Accommodation / Expenses: Mylan; Travel / Accommodation / Expenses: Daiichi Sankyo; Research grant / Funding (institution), Travel / Accommodation / Expenses: MacroGenics; Honoraria (self): Celltrion; Research grant / Funding (institution): OBI Pharma; Research grant / Funding (institution): Eisai; Research grant / Funding (institution), Mandatory publication support: Novartis; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Odonate Therapeutics; Research grant / Funding (institution), Travel / Accommodation / Expenses, Mandatory publication support: Roche/Genentech; Research grant / Funding (institution), Travel / Accommodation / Expenses, Mandatory publication support: Pfizer; Travel / Accommodation / Expenses: Puma Biotechnology; Travel / Accommodation / Expenses: Mylan; Travel / Accommodation / Expenses: Daiichi Sankyo; Research grant / Funding (institution), Travel / Accommodation / Expenses: MacroGenics; Honoraria (self): Celltrion; Research grant / Funding (institution): OBI Pharma; Research grant / Funding (institution): Eisai; Research grant / Funding (institution), Mandatory publication support: Novartis; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Odonate Therapeutics. L. Schwartzberg: Advisory / Consultancy, Research grant / Funding (institution): Helsinn; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Merck; Advisory / Consultancy: Heron Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Amgen; Speaker Bureau / Expert testimony: Coherus BioSciences; Speaker Bureau / Expert testimony: Puma Biotechnology. A. Stradella: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Celgene. S. Kroll: Shareholder / Stockholder / Stock options, Full / Part-time employment: Odonate Therapeutics. J. O’Connell: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Odonate Therapeutics; Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: inVentiv Health. T. Wei: Shareholder / Stockholder / Stock options, Full / Part-time employment: Odonate Therapeutics. E.A. Mittendorf: Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy: Genomic Health; Advisory / Consultancy: Merck; Advisory / Consultancy: Peregrine Pharmaceuticals; Advisory / Consultancy, Research grant / Funding (institution): Sellas Lifesciences; Advisory / Consultancy: Tapimmune. All other authors have declared no conflicts of interest.

Background Neoadjuvant chemotherapy offers the possibility to test chemo sensitivity in vivo. pCR is a good surrogate of survival. Other measures of pathological response include de residual cancer burden (RCB). The aim of our study is to assess prognostic factors of survival including RCB. Methods 488 breast cancer (BC) patients treated with NATC based on anthracyclines and taxanes with trastuzumab in HER-2 positive between 2009 and 2016 at a single Institution. Chi-square test was run for the univariate analyses and a cox-regression was performed regarding prognostic factors. Survival was calculated with Kaplan-Meier survival plots since the start of NATC to the first documented disease recurrence (DDFS) or overall survival (OS) by using IBM SPSS version 23. Results Mean age was 51.13 (24-84). After a follow up of 63 (4-129) months there have been 14 (2.9%) local recurrences; 55 (11.3%) distant recurrences and 56 deaths (11.4%), 50 due to BC progression (10.2%). In the univariate analyses those factors related to distant recurrence were histology ductal vs lobular: 14.2 vs 35.7%, p: 0.032; molecular subtype: luminal A (15.2%) vs luminal B (14.2%) vs luminal B Her2 (11.8%) vs HER2 enriched (7.7%) vs triple negative (TN) (22.8%), p: 0.042; TstageT0 (0%), T1(12.5%), T2(12.3%), T3 (18.8%) and T4 (23.9%), p: 0.006; N stage N0 (9.6); N1 (12.8), N2 (17.5) and N3(27.3%), p = 0.063;pTstage pT0 (8.5%), pTis (9.7) pT1a+b(7.5%)pT1c(20.3 %), pT2(21.8%), pT3 (29.2%) and pT4 (100%), p = 0.000; pN stage pN0 (8.2); pN1mic (0%), pN1 (16.8), pN2 (32.2) and pN3(42.3%), p = 0.000 and the RCB 0 (3.2%) vs I (7.1%) vs II (16.5%) vs III (23.4%), p: 0.0001. The estimated 5y DDFS was for RCB0: 100%; RCBI: 98%; RCBII: 85% and RCBIII: 68%. The HR for RCB was 1.4 (95%IC, 1.2-1.6), per subgroups the log rank was for luminal A: 3.4, p: 0.330; for luminal B: 10.6, p: 0.03; for luminal B Her2: 7.9, p: 0.04; for Her2 enriched: 25, p: 0.000 and for TN 16, p: 0.003. Conclusions In our large series the RCB is reproducible as a surrogate of survival special in those chemo sensitive tumors such as Her2 and triple negative ones. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

575 Background: NET is gaining more acceptances for the management of hormonal receptors (HR)-positive breast cancer (BC). To date, the decrease of Ki-67 and PEPI score are the only prognostic factors associated with relapse-free survival after NET. PAM50 is a validated prognostic test in newly diagnosed BC; however, its value in residual tumors after NET is currently unknown. Methods: We took tumor tissues from patients of a retrospective study of 119 postmenopausal women with HR-positive stage II-III BC. Patients were diagnosed from 1997 to 2009 and were treated with NET for a median duration of 8.5 months . Median age was 74 (63-88). After NET all patients underwent surgery (73% conservative). Adjuvant treatment were endocrine therapy in 100%, radiotherapy in 76.5% and chemotherapy 7%. Median follow-up from surgery was 112 months. Median follow-up from surgery was 112 months. We observed 26 (24%) of distant relapses and 75 deaths (44 without cancer). Median overall survival was 134.8 months. RNA was extracted from FFPE tumor tissues of surgical specimens. A panel of 55 BC-related genes, including the research-based PAM50 assay (subtypes, ROR-S and ROR-P pre-defined cutpoints), androgen receptor (AR), immune genes (CD8A, CD4, PDL1 and PD1). Uni- and multi-variable Cox models were used to evaluate the association of each variable with distance recurrence free interval (DRFI). Results: PAM50 subtype distribution: Luminal A 54.3%, Normal-like 24.3%; HER2-enriched 16,5%, Luminal B 1% and basal 1%. Distribution of ROR-S groups was Low 64%, medium 30%and high 6%. Distribution of PEPI score was: 0 in 43%, 3 in 37% and 6 in 20%. Among the different variables explored, PEPI score 0 (HR 0.27 [95%IC 0.09-0.79] p=0.001), low ROR-S (HR 0.39 [95%CI 0.17-0.91] p=0.001) and high AR expression (HR 0.71 [95CI 0.53-0.96] p=0.007) were significantly associated with lower DRFI in univariate analyses. After adjusting for PEPI (with or without Normal-like tumors), ROR-S and AR remained significantly associated with outcome. Conclusions: PAM50 ROR-S and AR expression in residual tumors after NET provide independent prognostic information beyond PEPI. With further validation, these biomarkers could help clinicians in the decision-making of adjuvant chemotherapy.

Background: Germline mutation screening of BRCA1 and BRCA2 genes is performed in suspected familial breast cancer cases, but a causative mutation is found in only 30% of patients. The development of additional methods to identify good candidates for BRCA1 and BRCA2 analysis would therefore increase the efficacy of diagnostic mutation screening. With this in mind, we developed a study to determine molecular signatures of BRCA1—or BRCA2—mutated breast cancers. Materials and Methods: Array-cgh (comparative genomic hybridization) and transcriptomic analysis were performed on a series of 103 familial breast cancers. The series included 7 breast cancers with a BRCA1 mutation and 5 breast cancers with a BRCA2 mutation. The remaining 91 cases were obtained from 73 families selected on the basis of at least 3 affected first-degree relatives or at least 2 affected first-degree relatives with breast cancer at an average age of 45 years. Array-cgh analyses were performed on a 4407 BAC-array (CIT-V8) manufactured by IntegraGen. Transcriptomic analyses were performed using an Affymetrix Human Genome U133 Plus 2.0 chip. Results: Using supervised clustering analyses we identified two transcriptomic signatures: one for BRCA1-mutated breast cancers consisting of 600 probe sets and another for BRCA2-mutated breast cancers also consisting of 600 probes sets. We also defined cgh-array signatures, based on the presence of specific genomic rearrangements, one for BRCA1-mutated breast cancers and one for BRCA2-mutated breast cancers. Conclusions: This study identified molecular signatures of breast cancers with BRCA1 or BRCA2 germline mutations. Genes present in these signatures could be exploited to find new markers for such breast cancers. We also identified specific genomic rearrangements in these breast cancers, which could be screened for in a diagnostic setting using fluorescence in situ hybridization, thus improving patient selection for BRCA1 and BRCA2 molecular genetic analysis.

e12112 Background: Pathological complete response (pCR) after neoadjuvant chemotherapy for BC has been related with survival, and the sequence of anthracyclines followed by taxanes (AT) has been the strategy to achieve this response. Some studies suggest that the reverse sequence (TA) might improve cancer outcomes. The aim of our study was to compare clinical response, toxicity and efficacy in terms of pCR rate (ypT0/pTis, ypN0) between both sequences Methods: A retrospective cohort study was designed. TA cohort received Docetaxel (100 mg/m2) x 4, followed by AC (60/600 mg/m2) x 4. AT cohort received the reverse sequence at the same doses. To be included, it was necessary to have received at least one cycle in the planned sequence. Logistic regression analysis was performed to obtain a model adjusted by age, menopausal status, tumor size, nodal status, grade, estrogen receptor (ER), progesterone receptor, and Ki67 Results: From June 2008 to December 2015, 135 consecutive patients with stage II – III HER2 negative BC were treated: TA (n = 48) and AT (n = 87). No significant differences in patient characteristics between groups were found, except for histological grade 3 (63.2% to AT vs. 35.4% to TA), and ER negative (41.4% to AT vs. 22.9% to TA). The pCR rate for TA was 16.7% (8 of 40) vs. 14.9% (13 of 74) for AT. Multivariate logistic regression analysis found OR = 3.65 to achieve pCR for TA (95%CI 1.03 – 12.94; p = .045). We also performed the same analysis for two clinical parameters of response: Neoadjuvant response index (NRI) with cut-off > 0.5 (OR 3.96, 95%CI 1.42-11.08; p = .009) and Clinical response (CR) > 50% (OR 3.65, 95%CI 1.03 – 12.94; p = .045). These parameters were correlated in our series with DFS (p = .011 to NRI and p = .00023 to CR) and OS (p = .034 to NRI and p = .0014 to CR) using the Kaplan-Meier method. No significant differences between rates of either, hospitalizations, neutropenia or dose intensity were found Conclusions: Sequence of T followed by A was slightly significantly more effective to achieve pCR as well as better clinical outcomes in our series of HER2 negative BC than classical sequence of A followed by T, and support the design of large prospective studies to confirm these results

To study lytic lesions in a patient with past history of renal cancer.A 62 year-old man was admitted to hospital for investigation of the cause of polyostotic bone pain.Brown tumors due to hyperparathyroidism turned out to be the cause of bone pain.Differential diagnosis is important in daily practice in order to provide a correct treatment for each condition.

e13530Background: brain metastases (BM) occur in 15-30% of patients with metastatic breast cancer (MBC). In spite of improvements in the treatment, the development of BM is still being a major limi...

e15159 Background: To analyze the prognostic value for survival of the absolute levels of serum testosterone in patients under the definition of CRPC (PSA and/or clinical progression with a testosterone level below 50 ng/dL). Methods: 49 patients were included in 4 non-hormonal first line phase II-III trials in our institution since August 2006 until Jan 2012 for metastatic CRPC. Inclusion criteria of those trials uniformly required castrate levels of testosterone. Survival was calculated since the date of entrance in the trial. Results: Median age was 71 years (53-89). 9/49 (18%) of the patients had visceral metastases. Median PSA was 66.7 U/L (0.1-936). Median testosterone level was 11.54 ng/dL (range 0.2-49.9). All patients had metastatic prostate cancer, previous treatment consisted of at least 2 hormonal maneuvers (adding or stopping antiandrogen for a wash-up period of 42 days for bicalutamide). All patients received at least one line of chemotherapy for CRPC as part of the trial or after the completion of the trial. Median survival was 21.85 months. For 26 patients with a serum testosterone level below the median value, median survival was 17 months and 35.45 months for those patients with a testosterone level over 11.51 ng/dL (p value 0.036). Conclusions: Testosterone serum levels even under castration level (below 50 ng/dL) were a prognostic factor for survival in patients with metastatic prostate cancer considered castration resistant.

e14104 Background: KRAS mutation has been established as a predictive marker of resistance to antiEGFR therapy in patients (pts) with colorectal cancer (CRC) but the role of BRAF is not yet clear. Both gene mutations have also been studied as prognostic factors but results are contradictory. AntiEGFR therapies impair evaluation of KRAS and BRAF as prognostic factors when overall survival is an endpoint. We hypothesized that if KRAS or BRAF were prognostic factors, they would influence time to relapse (TTR) after complete tumor resection. Methods: Patients who underwent surgery between 2007 and 2011 for stage II and III CRC were retrieved from our database. Codon 12 and 13 KRAS mutations and V600E BRAF mutation were analyzed. Clinical characteristics and mutation status were correlated with TTR. Results: We analyzed 170 pts with a median age of 66 (26 – 86) years. Tumors were located in the right colon in 27% of pts, in the transverse colon in 3%, in the left colon in 41%, and in the rectum in 29%. Most (55.3%) were stage III; 59% received adjuvant chemotherapy. KRAS and BRAF mutations were present in 66 (38.8%) and 5 (2.9%) pts respectively, and both were mutually exclusive. The most frequent KRAS mutations were: G12D (39.3%), G12V (27.2%), G13D (15.1%). Median TTR was 71 weeks (w) (95% CI 63-79). V600E BRAF mutation was the only factor associated with TTR. TTR was 42 w in tumors with the BRAF mutation and 74 w in wild-type tumors (p=0.041). Among KRAS mutations, KRAS G12V conferred a significantly longer TTR (100w) than the other subtype mutations (69 w; p=0.05). Conclusions: Our results suggest that V600E BRAF mutation is a negative prognostic factor in CRC, conferring a shorter time to relapse. Additionally, the KRAS G12V determines a different behavior among KRAS mutation tumors.

5595 Background: Patients with a head and neck squamous cell carcinoma (HNSCC) index tumor have a increased risk (2-4% per year) for appearance of a second malignant neoplasms (SMN) and higher risk for successive malignant tumors during the follow-up. The objective of our study was to validate this concept with data of patients included in the Surveillance Epidemiology and End Results (SEER) program (1973-2008). Methods: We performed a population-based cohort study of 149.328 patients with a primary oral cavity, oropharynx, hypopharynx and larynx squamous cell carcinoma index tumor, included in the SEER program, to analize the actuarial survival-free of second and successive tumors. A total of 11.948 (8%) patients had one or more malignant tumors before the diagnosis of HNSCC. Results: During the follow-up period, a total of 31.507 new SMN appeared. There was a progressive and significant increase in the risk of SMN. The annual hazard ratio for 2nd to 7th successive SMN was 2.3%, 2.7%, 3.9%, 5.4%, 8.9% and 19.1% annual risk respectively. Additionally 11 patients had 8th SMN. We observed a progressive increase in the risk of appearence of new malignant tumors located in and outside the aerodigestive tract. The increase in the risk of SMN was higher for tumors located in the aerodigestive tract than tumors located outside aerodigestive tract. It was a tendency towards the increase in the proportion of HNSCC with the appearance of new tumors, with a decrease in the proportion of the malignant tumors located in the lung and in locations outside the aerodigestive tract. There were significant differences inthe risk of SMN between second and third, third and fourth, fourth and fifth, and sist and seventh tumors (p

e15105 Background: Until recent developments in treatment of PPuCT (cabezitaxel, abiraterone) progressing after docetaxel, second line therapies were scarce. In our Hospital, Docetaxel as first lin...

e15091 Background: Patients with bladder tumors are at high risk of developing second urinary and non-urinary neoplasms. In addition, risk factors of cardiovascular and non-cardiovascular mortality such as smoking are common. We analyze the incidence of second tumors in conservatively managed patients with good prognosis invasive bladder cancer. Methods: From January 2000 to December 2010, 54 patients (9 women, 45 men) were treated with maximum transurethral resection (TUR). After TUR, 40 patients received either 3 cycles of chemotherapy (CT) with cisplatin 75 mg/m2 or carboplatin AUC 5, if creatinine clearance was below 55 mL/min, plus gemcitabine 1 gr/m2. 14 (26%) patients not candidates or not willing a cystectomy received concomitant chemoradiotherapy (CRT). A new TUR and biopsies were performed in all patients after completing the therapy and later biannually for the first year. Patients with cT4 tumors, other histology than transitional cell cancer and patients with hydronephrosis or multifocal carc...

10042 Background: Chemotherapy is the standard treatment in high risk advanced sarcomas. The role of HDCT/SCT is controversial in this patients (pt). We described our experience and long term resul...

Síndromes de càncer; Panell genètic; Proves genètiques Síndromes de cáncer; Panel de genes; Prueba genética Cancer syndromes; Gene panel; Genetic testing Importance Genetic testing of hereditary cancer using comprehensive gene panels can identify patients with more than one pathogenic mutation in high and/or moderate-risk-associated cancer genes. This phenomenon is known as multilocus inherited neoplasia alleles syndrome (MINAS), which has been potentially linked to more severe clinical manifestations. Objective To determine the prevalence and clinical features of MINAS in a large cohort of adult patients with hereditary cancer homogeneously tested with the same gene panel. Patients and methods A cohort of 1023 unrelated patients with suspicion of hereditary cancer was screened using a validated panel including up to 135 genes associated with hereditary cancer and phakomatoses. Results Thirteen (1.37%) patients harbouring two pathogenic mutations in dominant cancer-predisposing genes were identified, representing 5.7% (13/226) of patients with pathogenic mutations. Most (10/13) of these cases presented clinical manifestations associated with only one of the mutations identified. One case showed mutations in MEN1 and MLH1 and developed tumours associated with both cancer syndromes. Interestingly, three of the double mutants had a young age of onset or severe breast cancer phenotype and carried mutations in moderate to low-risk DNA damage repair-associated genes; two of them presented biallelic inactivation of CHEK2. We included these two patients for the sake of their clinical interest although we are aware that they do not exactly fulfil the definition of MINAS since both mutations are in the same gene. Conclusions and relevance Genetic analysis of a broad cancer gene panel identified the largest series of patients with MINAS described in a single study. Overall, our data do not support the existence of more severe manifestations in double mutants at the time of diagnosis although they do confirm previous evidence of severe phenotype in biallelic CHEK2 and other DNA repair cancer-predisposing genes. Contract grant sponsor: Supported by the Carlos III National Health Institute and Ministerio de Educación y Ciencia funded by FEDER funds–a way to build Europe (PI16/00563, PI16/01363, SAF2015-68016-R and CIBERONC); the Government of Catalonia (Pla estratègic de recerca i innovació en salut (PERIS), 2017SGR1282 and 2017SGR496); and the scientific foundation Asociación Española Contra el Cáncer.