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Background: Olaparib (O) is approved for the treatment of HER2[-] patients (pts) with early or metastatic breast cancer and a germline BRCA mutation. Nevertheless, there is no evidence that HER2[+] tumors are resistant to PARPi. Preclinical data support that HER2[+] cells are sensitive to PARPi and strongly suggest that PARP inhibition augments the efficacy of trastuzumab (T). To test whether PARPi is synergistic with anti-HER2 therapy, the OPHELIA study has assessed the efficacy and safety of O in combination with T in pts with HER2[+] germinal BRCA-mutated advanced breast cancer (ABC). Methods: OPHELIA (NCT03931551) is an open-label, multicenter, single-arm, phase II trial. The study enrolled pts aged ≥18 years diagnosed of HER2[+] ABC with germinal deleterious mutations in BRCA1 or BRCA2 who had received at least one prior systemic regimen for advanced disease (including a pertuzumab- or trastuzumab emtansine based regimen). Pts received O (300 mg oral, twice daily) plus T (either loading dose of 8 mg/kg IV infusion, and subsequent 3-weekly doses of 6 mg/kg IV infusion; or 600 mg SC injection, on day 1 of every 21-day cycle) until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint was investigator-assessed clinical benefit rate (CBR) for at least 24 weeks as per RECIST v.1.1. Secondary endpoints included overall response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS); and safety and tolerability as per NCI-CTCAE v.5.0. The primary analysis evaluated CBR (H0: ≤5%; H1: ≥30%) based on exact binomial test. Sample size was designed to attain a 90% power at 10% one-sided alpha level. Results: From Mar 25, 2019, through Mar 2, 2022, 5 pts (from a total of 42 pts evaluated) were enrolled at 17 sites in Spain. Median age was 37.0 (range 32–54) years, 1 (20.0%) patient was male, 4 (80.0%) pts carried germinal BRCA2 mutations, 4 (80.0%) pts had received ≥ 3 advanced disease treatments lines, and 4 (80.0%) pts presented ≥ 2 metastatic sites. At data cutoff (Mar 2, 2022), with a median follow-up of 18.7 months (min: 11.7; max: 22.1), 40.0% of pts remained on therapy. CBR at 24 weeks was 80.0% meeting the primary endpoint (4 of 5 pts; 95% CI, 28.4% to 99.5%, p< 0.001). ORR (1 complete and 2 partial responses) was 60.0% (95% CI, 17.4% to 94.7%), and median DoR was 3.8 months (95% CI, 2.5 to 8.3 months). Two (40.0%) pts had PFS events due to disease progression at 5.2 and 1.2 months, respectively. Rest of pts were treated for 5.5, 11.2, and 19.0 months. There were 2 (40.0%) deaths at 14.0 and 18.5 months. The most common non-hematological treatment emergent adverse events (TEAEs) of any grade (G) were fatigue (60.0%; 0% G≥3), nausea (60.0%; 0% G≥3), vomiting (40.0%; 0% G≥3), and back pain (40.0%; 0% G≥3). Anemia (40.0%; 20.0% G≥3) and lymphopenia (40.0%; 20.0% G≥3) were the most frequent hematological TEAEs. One (20.0%) patient discontinued treatment because of a drug-related TEAE (leukopenia). A dose reduction of O was reported in 1 (20.0%) patient. No treatment-related deaths were reported. Conclusions: HER2 overexpression in germline BRCA-mutated ABC is infrequent. The activity observed in these 5 pts indicates that O+T combination might be of help in this group of pts. We strongly believe that randomized data are not needed, and RWE studies might help us to understand the real activity of this combination. Toxicity was as expected. Citation Format: José E. Alés-Martínez, Judith Balmaña, Pedro Sánchez-Rovira, Francisco Javier Salvador Bofill, José Ángel García-Sáenz, Isabel Pimentel, Serafin Morales Murillo, Adela Fernández, Ainhara Lahuerta Martínez, Neus Ferrer, Pilar Zamora, Begoña Bermejo, Tamara Díaz-Redondo, María Helena Lopez-Ceballos, María Galán, Andrea Malfettone, Laura Calabuig, Miguel Sampayo-Cordero, José Manuel Pérez-García, Javier Cortés, Antonio Llombart-Cussac. Olaparib plus Trastuzumab in HER2[+] BRCA-Mutated Advanced Breast Cancer Patients: The OPHELIA Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-29.

Background: This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavilypretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/ HER2(-)) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017. Patients and methods: Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR+/HER2(-) mBC who had progressed on >= 4 treatments for advanced disease were eligible. Results: A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7-7.0) and the median overall survival was 19.0 months (95% CI 16.4-21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus, This study was sponsored by Biomedical Research Foundation of the Hospital Clinico San Carlos (Madrid, Spain). The study was funded by an investigator sponsored research grant (WI236789) from Pfizer.

Pre-operative chemoradiotherapy using a 5-fluorouracil (5-FU)/cisplatin backbone is widely used to improve surgical outcomes in locoregional oesophageal cancer patients, despite a non-negligible failure rate. We evaluated intensification of this approach to improve patient outcomes by adding cetuximab to induction 5-FU/cisplatin/docetaxel (TPF) and to chemoradiotherapy in a phase II study. Between November 2006 and April 2009, 50 patients with stage II–IVa squamous cell carcinoma (SCC) or adenocarcinoma of the oesophagus or gastro-oesophageal junction initiated three TPF/cetuximab cycles. Six weeks later, patients with response or stabilisation initiated 6 weeks of cisplatin/cetuximab/radiotherapy, followed by surgery. The primary objective was the clinical complete response (cCR) rate after induction therapy plus chemoradiotherapy in intent-to-treat patients. Thirty-eight patients were evaluable after chemoradiotherapy, 84% of whom showed disease control. Six patients (12%) achieved a cCR, with a 54% overall response rate. Twenty-seven patients underwent surgery, 11 of whom (22%; nine SCC, two adenocarcinoma) had a pathological CR (41%). Fifteen patients were alive after a median follow-up of 23.2 months. Median progression-free survival was 12.2 months (95% confidence interval [CI] 1.7–22.8). Median overall survival was 23.4 months (95% CI 12.2–36.6) and was significantly longer among the 22 patients with complete resection than in the five patients without (42.1 vs. 24.9 months; p = 0.02, hazard ratio: 3.6, 95% CI 1.1–11.6). The toxicity profile was acceptable. Neoadjuvant cetuximab/TPF followed by chemoradiotherapy in locoregional oesophageal carcinoma patients is feasible and offers a modest response rate in this trial. The results of combining trimodality neoadjuvant treatment with cetuximab are consistent with the literature. Registration: The study is registered at ClinicalTrials.gov (NCT00733889).

e12539 Background: The Notch signaling pathway plays an important role in cell-differentiation, survival, proliferation, stem-cell renewal, and in determining cell fate during development and morphogenesis. The dysregulation of the Notch pathways contributes to carcinogenesis, cancer stem cell renewal, angiogenesis, and chemo-resistance. Elevated levels of Notch receptors and ligands have been associated with cancer-progression and poor survival. A less explored function of Notch pathways in cancer is their role in leukocyte homing and activation. Understanding their role and relationship with immune infiltrates is an area of interest in cancer research. Methods: The expression of four different Notch genes (Notch1, Notch2, Notch3 and Notch4) was explored in relation with A luminal breast cancer patient outcome using transcriptomic data (Affymetrix dataset, exploratory cohort) and the METABRIC study (validation cohort). The TIMER online tool was used to explore the association of the identified notch and immune infiltration, and the TCGA and METABRIC studies to analyze the correlation between notch1 - 4 expression and genomic signatures of immune activation. Results: We identified 2 individual genes called Notch1 and Notch2, which predict favorable prognosis in luminal A breast cancer. Their expression positively correlated with the presence of immune infiltrates within the tumor (dendritic cells, CD4+ T cells, neutrophils, CD8+ T cells and B cells), with markers of T cell activation and antigen presentation, and with gene signatures of immune surveillance (cytotoxic T lymphocyte activation and IFN gamma signature). By contrast Notch3 and Notch4 which predicted for detrimental outcome were not associated with any of these parameters. Conclusions: Our analysis identifies a Notch signature composed of 2 genes with potential to recognize immune infiltrated and activated A luminal phenotype breast cancers with favorable prognosis.

BACKGROUND: Factors by which breast cancer cells invade blood and lymphatic capillaries and metastasize regional lymph nodes and distant sites are not well understood. Genetics, molecular subtype, epidemiological, mechanical and pathological factors are being considered. Once breast cancer cells invade lymphatic or blood vessels the route of spread is still unclear. Cells could access the systemic circulation through the sentinel lymph node or directly avoiding the lymph node step. Molecular subtype is one of the most important factors associated with the risk of metastases. Our objective is to determine the influence of immunophenotype and the sentinel lymph node (SLN) status to predict the risk of locoregional relapses and distant metastases in early breast cancer. In our center we are using a molecular technique (OSNA) to ascertain if there is sentinel lymph node involvement, this technique creates a new continuous variable, Total Tumor Load (TTL), defined as the total number of CK19 mRNA copies in all positive SLN (copies/microL), indicating the total tumor volume of axillary tumor involvement. METHODS: Clinicopathological and follow up data were obtained from all patients with early breast cancer treated with Tumorectomy (Tx) and Sentinel Lymph Node (SLN) assessed by OSNA with the decision to proceed to ALND based on Z0011 criteria and systemic therapy between 2011 and 2018 at our center (J Clin Oncol 37, 2019 (suppl; abstr 564)) RESULTS: 304 breast cancer patients underwent Tx and SLN assessed by OSNA followed by systemic therapy with an average follow-up of 64.9 months. SLN was positive in 122 cases and negative in 182. SLN negative patients were Luminal A (LA) 58%, Luminal B (LB) 14%, HER2 10% and Triple-Negative (TN) 7%. SLN positive patients were LA 52%, LB 35%, HER2 7% and TN 5%. Mean TTL was 136,244 copies (see table). As of now, 11 patients have had recurrence (locoregional relapse and distant disease): 6 of them with positive SLN (54,54%) and 5 with negative SLN (45,45%). A total of 4 patients have had locoregional relapse, two of them with negative SLN (50%) both non luminal tumors (1 HER2, 1 TN), and 7 have had distant disease, three of them with negative SLN (43%). Only one patient has died from metastatic breast cancer (HER2 positive, SLN negative). CONCLUSIONS: 1. In our series, almost half of the patients (45%) with recurrence were negative SLN. 2. The probability of recurrence when the sentinel lymph node is negative is higher in HER2 and TN tumors (60%). 3. The probability of recurrence when the SLN is positive is higher in luminal tumors (66,6%). 4. Luminal tumors with positive SLN and large volume axillary involvement (median 1.419.450 copies) have a higher probability of recurrence (statistically significant) than luminal tumors with positive SLN and small volume axillary involvement (median 131.479 copies). PATIENTS AND OUTCOMES VARIABLE N=304Number of cases (n,%)Median age, range (years)LOCOREGIONAL RELAPSEMETASTASIC BREAST CANCEREXITUSMean TTL with NO recurrenceMean TTL with recurrencePOSITIVE SLN122 (40%)59,8 (33-87)2 (1,63%)4 (3,27%)0By ImmunophenotypeLuminal A64 (52,4%)59,3 (36-87)1 (1,5%)2 (3,1%)0371.5592.838.333Luminal B43 (35,2%)59,5 (36-84)1 (2,32%)00258.6221600HER29 (7,3%)61 (33-80)01 (11,1%)021.582640Triple Negative6 (5%)59,6 (50-80)01 (16,6%)0108.181184.000NEGATIVE SLN182 (60%)59,3 (27-89)2 (1,09%)3 (1,64%)1 (0,5%)By ImmunophenotypeLuminal A106 (58%)59,3 (33-82)000Luminal B43 (14,1%)59,5 (36-89)1 (2,32%)1 (2,32%)0HER219 (10,4%)59,3 (40-82)01 (5,2%)1 (5,2%)Triple Negative14 (7,7%)59,4 (27-85)1 (7,14%)1 (7,14%)0 Citation Format: José Enrique Alés-Martínez, Raquel Tur, Juan Parra, Ana De Castro, Jaime Ceballos, Rocío Martín, Rosa Ana Marcos, Paz Blanco, MJose Velasco. Cancer phenotype is the key factor in axillary involvement and distant recurrence in early breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-02-03.

Imaging in oncology is an essential tool for patient management but its potential is being profoundly underutilized. Each of the techniques used in the diagnostic process also conveys functional information that can be relevant in treatment decision making. New imaging algorithms and techniques enhance our knowledge about the phenotype of the tumor and its potential response to different therapies. Functional imaging can be defined as the one that provides information beyond the purely morphological data, and include all the techniques that make it possible to measure specific physiological functions of the tumor, whereas molecular imaging would include techniques that allow us to measure metabolic changes. Functional and molecular techniques included in this document are based on multi-detector computed tomography (CT), 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET), magnetic resonance imaging (MRI), and hybrid equipments, integrating PET with CT (PET/CT) or MRI (PET-MRI). Lung cancer is one of the most frequent and deadly tumors although survival is increasing thanks to advances in diagnostic methods and new treatments. This increased survival poises challenges in terms of proper follow-up and definitions of response and progression, as exemplified by immune therapy-related pseudoprogression. In this consensus document, the use of functional and molecular imaging techniques will be addressed to exploit their current potential and explore future applications in the diagnosis, evaluation of response and detection of recurrence of advanced NSCLC.

564 Background: The study of sentinel lymph nodes (SLN) assessed by One Step Nucleic Acid Amplification (OSNA, Sysmex, Kobe, Japan) creates a new variable, Total Tumor Load (TTL). This variable is defined as the total number of CK19 mRNA copies in all positive SLN (copies/microL). The latest edition of the Spanish Oncological Gynecology Society (SEGO) Guideline (2017) proposes a complete axillary lymph node dissection (ALND) when TTL is 15,000 copies or more in early breast cancer. In our center we are using OSNA to ascertain if there is axillary node involvement but the decision to proceed to ALND is based on Z0011 criteria. We want to determine if there is a correlation between clinical outcomes and TTL values, between TTL and pathological variables and if TTL is a useful tool to decide when to complete an ALND. Methods: Clinicopathological and follow up data were obtained from all patients with invasive breast cancer and SLN assessed by OSNA between 2011 and 2017 at our center. Results: A total of 321 patients underwent SNB assessed by OSNA with an average follow-up of 56 months. 320 were female and 1 male. Age range 27-89 years (mean 58.9). 85 % were ductal, 10 % lobular and 5 % other. 53.5% were luminal A, 28.66% luminal B, 7.78%, triple negative, 4.3%, Her2 positive and 4.3%. luminal B-Her2 positive.TTL was equal to 0 in 183 cases and greater than zero in 138 cases.71 cases showed a TTL higher than 15,000 copies. Only 21 cases met Z0011 criteria and had ALND. As of now, 3 patients have had locoregional relapse and 8 metastatic disease. 12 have died, only two from metastatic breast cancer. Conclusions: Using Z0011 criteria, we have adequate clinical outcomes with a low rate of ALND; If we had based the axillary management on TTL values we would have multiplied the number of ALND by a factor of 3.3 (from 21 to 71); We have observed a tendency to higher TTL in luminal phenotypes and to lower TTL in HER2 positive and triple negative subtypes; Work is in progress to increase our sample size.

e20648 Background: The molecular study of non-small cell lung cancer (NSCLC) allows for targeted treatment. EGFR and ALK alterations have been observed in 14% and 5% of Caucasian patients (p) respectively. These alterations are mainly detected in women with adenocarcinoma (ADC) and non-smokers. In a non-selected (all comers) NSCLC population from Ávila (Spain) we found a different profile. Methods: We collected data from 185 consecutive p the Pathology Department database of Hospital Nuestra Señora de Sonsoles from 2012 to 2017. All p were tested for EGFR and ALK. Analyses were done with Cobas or Therascreen tests. Results: EGFR mutations were found in 11 p out of 185 (6.7%). Histology was ADC in 8 p (72.7%) and squamous cell carcinoma (SC) in 3 p (27.3%). Male (m) & smokers: 4/11 (36,4%). The type of mutation was: Exon 20: 3 p (27.3%). 2 m and 1 female (f). 2 smokers and 1 former smoker. 2 ADC and 1 SC; Del 19: 4 p (36.4%). 1 m and 3 f. 1 non-smoker, 2 former smokers and 1 smoker. 3 ADC and 1 SC; Exon 21: 4 p (36,4%). 2 m and 2 f. 3 non-smokers and 1 smoker. 3 ADC and 1 SC. All p. received treatment with 1st generation anti-EGFR drugs for a median 6.4 months (m). Progression Free Survival was 6.39 m (exon 20: 5.1 m; Del 19: 6.5 m; exon 21: 7.2 m). Overall survival was 18.0 m (exon 20: 26.1 m; Del 19: 18.2 m; exon 21: 11.8 m). ALK translocation was found in 5 p out of 158 (3.2%). Histology was ADC in 3 p (60%) (all f, 2 non-smokers and 1 former smoker) and SC in 2 p (40%) (2 smoker m.) Conclusions: Although the small sample size prevents definitive conclusions, EGFR mutations in exon 20 are more frequent in smokers and mutations in exon 21 in non-smoking patients with ADC. ALK translocation was observed independent of sex, tobacco or histologic type. For EGFR and ALK alterations, screening based on sex or pathology would have missed findings with therapeutic implications. We conclude it is important to extend the analysis of molecular alterations to all patients with NSCLC since more of them could benefit from targeted drugs.[Table: see text]

BACKGROUND The study of sentinel lymph nodes (SLN) assessed by One Step Nucleic Acid Amplification (OSNA, Sysmex, Kobe, Japan) creates a new variable, Total Tumor Load (TTL). This variable is defined as the total number of CK19 mRNA copies in all positive SLN (copies/microL). The latest edition of the Spanish Oncological Gynecology Society (SEGO) Guideline (2017) proposes complete axillary lymph node dissection (ALND) when TTL is 15,000 copies or more in early breast cancer. In our center we are using OSNA to ascertain if there is axillary node involvement but the decision to proceed to ALND is based on Z0011 criteria. We want to determine if there is a correlation between clinical outcomes and TTL values, between TTL and pathological variables and if TTL is a useful tool to decide when to complete an ALND. METHODS Clinicopathological and follow up data were obtained from all patients with invasive breast cancer and SLN assessed by OSNA between 2011 and end of 2016 at our center. RESULTS A total of 277 patients underwent SNB assessed by OSNA with an average follow-up of 56.4 months. 276 were female and 1 male. Age range 27-88 years (mean 58,7). 86,2 % were ductal, 10,8 % lobular and 2,8 % other. 51.9% were luminal A, 51.98% luminal B, 28.51%, triple negative, 5% Her2 positive and 5% luminal B-Her2 positive. TTL was equal to 0 in 155 cases and greater than zero in 122 cases.68 cases showed a TTL higher than 15,000 copies. Only 19 cases met Z0011 criteria and had ALND. As of now, 3 patients have had locoregional relapse (TTL = 0 in 2 cases and 18,000 copies in one) and 5 metastatic disease (none with simultaneous locoregional recurrence). 7 patients have died (one from metastatic breast cancer, 1 febrile neutropenia, 2 septic shock unrelated to chemotherapy, 2 from other tumors, 1 encephalopathy). BASELINE DATA N=277VARIABLE N%AGE,MEDIAN RANGE 58,7 (27-88) TUMOR TYPEDuctal23986,2 Lobular3010,8 Others82,8IMMUNOPHENOTYPELuminal A14451,98 Luminal B7928,51 Luminal B-HER2145 HER2 positive14 Triple Negative269,3TOTALL TUMORAL LOAD (TTL)=015556 >012244AXILLARY LYMPH NODE DISECTIONS 196,8TTL>15000 6824,5LOCOREGIONAL RELAPSES 31 CONCLUSIONS 1. Using Z0011 criteria, we have adequate clinical outcomes with a very low rate of ALND and locoregional recurrences. 2. If we had based the axillary management on TTL values we would have multiplied the number of ALND by a factor of 2,7 (from 18 to 50). 3. We have observed a tendency to higher TTL in luminal phenotypes and to lower TTL in HER2 positive and triple negative subtypes. 4. Work is in progress to increase our sample size. Citation Format: Tur R, Parra J, Martin R, Alés-Martinez JE. No relationship of axillary total tumor load (TTL) by PCR (OSNA) in early breast cancer and local and distant clinical outcomes [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 P3-03-17.

e12574Background: The study of sentinel lymph nodes (SLN) assessed by One Step Nucleic Acid Amplification (OSNA, Sysmex, Kobe, Japan) creates a new variable, Total Tumor Load (TTL). This variable i...

Background: The study of sentinel lymph node (SNL) assessed by OSNA provides a new variable, Total Tumoral Load (TTL).This variable is defined as the amount of CK19 mRNA copies number in all positives SLN. TTL has been showed to predict the axillary node status and has been analysed to determine its usefulness in the axillary surgical management. Based on TTL values different cut-off points have been proposed (last 25.000 copies) to establish a new tool to practice axillary lymph node dissection (ALND). We present the follow-up data of at least 5 years of breast cancer patients who underwent ALND according, strictly, to Z0011 trial criteria. We hypothesized that there will be no correlation between TTL and locoregional relapse if Z0011 are followed. Methods: Clinicopathological and follow up data were obtained from patients with invasive breast cancer and SLN assessed by OSNA between 2011 and 2012 at Complejo Asistencial de Ávila, Spain. ALND was decided based on Z0011 study criteria independently of TTL. All patients have been followed for a minimun of 5 years. Results: A total of 106 patients underwent SN assessed by OSNA, age range 27-85 years (mean 58,96). Of them 90% were ductal, 7,5% lobular and 2% others. By inmunophenotype: Luminal A 55%, Luminal B 28%, Triple Negative 9,4%, Her2 positive 3,7% and Luminal B-Her2 positive 2,8%. TTL was equal to zero in 58 cases and greater than zero in 48 cases with a range of 280-2.700.000 copies. Only 5 cases met ALND criteria (average TTL 68.164). Average TTL in cases without ALND was 111.000. For the time being, none of them has had locoregional relapse (median follow up 65 months). 3 patients have died one metastatic desease (Negative SN), one uterine cervix cancer and one neutropenic fever. Baseline and outcomes dataVARIABLE N%Age, years (median, range) 59 (27-85) Tumour TypeDuctal9690,5 Lobular87,5 Others21,8InmunophenotypeLuminal A5955,6 Luminal B3028,3 Luminal B-Her232,8 Her243,7 Triple Negative109,4Total Tumoral Load (TTL)=05854,7 >04845,2Axillary Lymph Node Dissection (ALND) 254,7TTL >25.000 2321,7Locoregional relapse 00Overall Survival 95,2 Conclusions: -Using Z0011 criteria and OSNA no locoregional recurrence has been observed so far. -TTL did not predict risk of recurrence -If we had based axillary management only on TTL values (i.e higher than 25.000 copies) we would have unnecessarily increased the number of lymphadenectomies in a 22%. This is an ongoing study that designed to increased the sample size and obtain longer follow-up data. Citation Format: Tur R, De Grado C, Martin MR, De Castro J, Filipovich E, Segovia B, Ceballos J, Parra J, Revestido R, Alés-Martínez JE. Relationship of axillary total tumor load (TTL) by OSNA (one step nucleic acid amplification) in early breast cancer and clinical outcomes using strict Z0011 study criteria for axilla management [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 P3-01-19.

Breast cancer is a burden for western societies, and an increasing one in emerging economies, because of its high incidence and enormous psychological, social, sanitary and economic costs. However, breast cancer is a preventable disease in a significant proportion. Recent developments in the armamentarium of effective drugs for breast cancer prevention (namely exemestane and anastrozole), the new recommendation from the National Institute for Health and Care Excellence to use preventative drugs in women at high risk as well as updated Guidelines from the US Preventive Services Task Force and the American Society of Clinical Oncology should give renewed momentum to the pharmacological prevention of breast cancer. In this article we review recent major developments in the field and examine their ongoing repercussion for breast cancer prevention. As a practical example, the potential impact of preventive measures in Spain is evaluated and a course of practical actions is delineated.

e12062 Background: Prosigna is a standardized test based on the PAM50 gene signature which provides information on intrinsic subtype and risk of recurrence (ROR) score predicting 10y recurrence probability (NanoString Technologies, Inc., Seattle, WA). We evaluated Prosigna’s impact on adjuvant treatment decision beyond immunohistochemistry (IHC) testing. Methods: 125 pre- and postmenopausal EBC patients with ER+, HER2-, pT1-T2 pN0/pN1mi were enrolled (12 centers; 8/2015-11/2016). FFPE specimens were centrally analyzed using Prosigna to classify patients according to the intrinsic tumor subtype and ROR score. The primary endpoint was the impact of the Prosigna test on adjuvant treatment decision. Results: 64% of tumors were classified by PAM50 as Lum A, 35% as Lum B, 0% Basal, 1% HER2-E. The intrinsic subtype concordance between immunohistochemistry (IHC) and Prosigna (n = 119) was 61.3%. In Lum B tumors by IHC the discordance rate was the highest (48% were reclassified as Lum A by Prosigna) as shown in the Table. ROR risk groups were as follows: ROR low (54; 43%), ROR interm. (38; 30%), and ROR high (33; 27%). Prosigna results led to a treatment recommendation change in 49 (39%) patients. In the 76 (61%) cases with the initial recommendation of Hormonal Therapy (HT) alone the final decision changed to chemotherapy (CT)+HT (CHT) in 24 (32%) patients. In the 49 (39%) cases in which the initial recommendation was CHT the final decision changed to HT in 25 (51%) patients. Among the 38 patients with Prosigna intermediate risk, 21 (55%) were allocated to HT. Conclusions: In this prospective decision impact study, Prosigna results led to a 39% change in adjuvant therapy indication. Patients with initial indication of CHT were changed to HT alone in > 50% of cases. Thus, Prosigna results influenced the treatment decisions and reinforced its clinical utility in real-world settings. The intrinsic subtype classification based on IHC didn’t show to be an adequate surrogate for the genomic subtypes as determined by Prosigna. [Table: see text]

Purpose Exemestane, a steroidal aromatase inhibitor, reduced invasive breast cancer incidence by 65% among 4,560 postmenopausal women randomly assigned to exemestane (25 mg per day) compared with placebo in the National Cancer Institute of Canada (NCIC) Clinical Trials Group MAP.3 (Mammary Prevention 3) trial, but effects on quality of life (QOL) were not fully described. Patients and Methods Menopause-specific and health-related QOL were assessed by using the four Menopause-Specific Quality of Life Questionnaire (MENQOL) domains and the eight Medical Outcomes Study Short Form Health Survey (SF-36) scales at baseline, 6 months, and yearly thereafter. MENQOL questionnaire completion was high (88% to 98%) in both groups at each follow-up visit. Change scores for each MENQOL and SF-36 scale, calculated at each assessment time relative to baseline, were compared by using the Wilcoxon rank-sum test. Clinically important worsened QOL was defined as a MENQOL change score increase of more than 0.5 (of 8) points and an SF-36 change score decrease of more than 5 (of 100) points from baseline. Results Exemestane had small negative effects on women's self-reported vasomotor symptoms, sexual symptoms, and pain, which occurred mainly in the first 6 months to 2 years after random assignment. However, these changes represented only a small excess number of women being given exemestane with clinically important worsening of QOL at one time or another; specifically, 8% more in the vasomotor domain and 4% more each in the sexual domain and for pain. No other between-group differences were observed. Overall, slightly more women in the exemestane arm (32%) than in the placebo arm (28%) discontinued assigned treatment. Conclusion Exemestane given for prevention has limited negative impact on menopause-specific and health-related QOL in healthy postmenopausal women at risk for breast cancer.

e11513 Background: Two targeted agents, trastuzumab and lapatinib, enhance apoptosis in Her2-positive breast cancer cells. After progression to trastuzumab, the combination of lapatinib and capecit...

e21521Background: In our institution, median age of patients with lung cancer is 71. We decide to study how are treated patients over 80 years. Methods: We performed a retrospective observational s...

BACKGROUND: Several aromatase inhibitor studies have reported variations in the inhibitory potency of these agents that could lead to differences in clinical outcomes. In the current study, the authors formally evaluated the activity of anastrozole and exemestane in postmenopausal women with hormone-responsive, advanced breast cancer. METHODS: Postmenopausal women who had measurable disease according to Response Evaluation Criteria in Solid Tumors and had not received previous endocrine therapy for advanced breast cancer were randomized to receive either oral exemestane 25 mg daily or oral anastrozole 1 mg daily until they had disease progression. The primary endpoint was the objective response rate (ORR), and secondary endpoints included the clinical benefit rate (CBR), time to progression (TTP), overall survival, and safety. Crossover to the other aromatase inhibitor was permitted at the time of disease progression; ORR, CBR, and TTP after second-line treatment also were explored. RESULTS: In total, 103 patients were enrolled. The median patient age was 71.6 years, 52.4% of patients had visceral disease, and 75.8% of patients had ≥2 disease sites. Half of the patients had received previous tamoxifen, and 60% had received previous chemotherapy. The efficacy observed in the exemestane and anastrozole groups was an ORR of 36.2% and 46%, respectively; a CBR of 59.6% and 68%, respectively, and a TTP of 6.1 months and 12.1 months, respectively. At progression, 28 patients crossed over to the other aromatase inhibitor, including 16 patients who switched to exemestane (CBR, 43.7%; TTP, 4.4 months) and 12 patients who switched to anastrozole (CBR, 8.3%; TTP, 2 months). Both drugs were generally well tolerated, and no study drug-related serious adverse events were reported. CONCLUSIONS: In this phase 2 randomized trial, no significant differences in clinical activity were observed in favor of exemestane to justify a superiority phase 3 trial design in the first-line setting. Cancer 2012;. © 2011 American Cancer Society.

Background: Exemestane, a steroidal aromatase inhibitor, reduced the incidence of invasive breast cancers by 65% among 4560 post-menopausal randomized to exemestane or placebo for 5 years on MAP.3. Differences in quality of life (QOL) were judged to be minimal, but only summary information was reported. Purpose: To provide more detailed information about effects of exemestane on menopause-specific and health-related qualities of life. Method: Participation in quality of life assessment was an eligibility criterion. Menopause-specific and health-related qualities of life were assessed using the MENQOL (4 scales; physical, vasomotor, psychosocial, sexual) and SF-36 (8 scales; physical health, role function — physical, bodily pain, general health, vitality, social function, role function — emotional, mental health, and 2 summary scales) instruments, respectively at baseline, 6 months and then yearly after randomization. Compliance with QOL questionnaire completion at each follow-up visit ranged from 93–98%, and did not differ by group. Change scores for each MENQOL and SF-36 scale, calculated for each assessment time relative to baseline, were compared using the Wilcoxon Rank-Sum test. Summary scores were used to summarize the QOL scores observed at each time point for each SF-36 dimension and overall mental (MCS) and physical component summaries (PCS) and MENQOL domains. Clinically important worsening of MENQOL change scores was defined as an increase of ≥0.5/8 points. SF-36 change scores were considered worsened if scores decreased by ≥ 5 points from baseline. Results: Both groups were balanced on scores for MENQOL and SF-36 at baseline. Median follow-up was 35 months and the proportion of women who stopped study medication early for toxicity reasons was 15% in the exemestane arm and 11% in the placebo arm. There was a statistically significant difference in change scores for vasomotor symptoms among women on exemestane during the first 4 years (p-values Conclusion: Our assessment that early differences in vasomotor symptoms and pain were probably not clinically important is supported by the observation of no between-group differences when overall physical and mental health-related QOL changes were compared. Exemestane does not appear to have a major negative impact on the quality of life among these women. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S6-1.

Injection of the bacterial superantigen Staphylococcus aureus enterotoxin B (SEB) into mice provokes a rapid expansion and subsequent contraction of the pool of SEB-reactive T cells bearing T cell receptor (TcR) V beta 8 gene products. Given that interleukin 2 (IL-2) stimulates proliferation, abolishes anergy, and counteracts apoptotic cell death in T cells in vitro, we tested whether the IL-2 synthesis inhibitor cyclosporin A (CsA) or a vaccinia virus recombinant releasing high amounts of human IL-2 modulate SEB responses in vivo. Surprisingly, neither IL-2 nor CsA were able to change the in vivo kinetics and magnitude of SEB-induced expansion, unresponsiveness to SEB, and peripheral clonal deletion of T cells expressing products of the SEB-reactive TcR V beta 8 gene family. In accord with these in vivo observations, IL-2 is incapable of reversing "anergy" and apoptotic cell death of V beta 8+ SEB-reactive T cells isolated from SEB-primed mice in vitro. Accordingly, upon SEB injection V beta 8+ T cells expand rapidly, without expressing IL-2 receptor (IL-2R)alpha chains in vivo, although SEB induces IL-2R alpha in vitro. Altogether, these results indicate that the IL-2/IL-2R-mediated pathway is not involved in T cell repertoire modulation by bacterial superantigens. Moreover, the data suggest that unresponsiveness of V beta 8+ T cells from SEB-primed mice is not a reversible process, but involves an unreversible commitment to programmed cell death. Absence or presence of IL-2 responsiveness could be a hallmark to distinguish truly reversible anergy and peripheral clonal deletion.

638 Background: Head-to-head comparison of a steroidal aromatase inhibitor (AI) (E) vs. a non-steroidal AI (A) with crossover at the time of progression to evaluate the sequence of administration. Principal and secondary objectives were overall response rate (ORR), clinical benefit (CB) and time to progression (TTP). Methods: Postmenopausal pt with measurable ABC and positive HR, were stratified [previous tamoxifen (tam) (yes vs. no), previous chemotherapy (ct) (yes vs. no) and stage (IIIb vs. IV)], and randomized to E (25mg/day), or A (1mg/day) until progression. As per Simon’s test, with a p1 of 25% ORR and a p0 of 10% ORR, α and β errors 0.05 and 10%, 50 pt per arm were needed. Results: 103 (51 vs. 52) pt were recruited between 2002 and 2004. Main pt characteristics: median age 70 and 73 years, 82 vs. 88% stage IV, 12 vs. 17% previous ct, 51 vs. 50% previous tam, median size of lesions of 5 vs. 4 cm, mean number of lesions of 1.4 in both arms. Most frequent site of lesions were breast (33 vs. 35%), lymph nodes (22% vs. 25%) and connective tissue (27% vs. 23%). Efficacy: For initial treatment ORR was 37% (CI95% 24–51) in arm E vs. 52% (CI95% 38–66) in arm A (p= 0.151). 47% of pt in E vs. 60% in A presented CB (p=0.202). Mean TTP for arm E was 8.1 months (m) (1.1–15.2) and for arm A was 12.1 m (6.6–17.6) (p=0.4716). 11 pt (arm E) and 12 (arm A) crossed-over after progression. Following crossover mean TTP for E was 4.4 m (3.7–5.1) and for second line A was 1.9 m (0.1–3.7) (p=0.0172). Conclusions: E and A seem to be equivalent in terms of efficacy as first treatment for postmenopausal pt with ABC and positive HR. We suggest a possible advantage of the steroidal AI, exemestane, following disease progression on the non-steroid AI anastrozole. [Table: see text]

LBA504 Background: Limited efficacy and serious toxicities have limited uptake of tamoxifen or raloxifene as preventatives of breast cancer. Aromatase inhibitors (AIs) prevent contralateral breast cancers more than tamoxifen in adjuvant trials and have fewer serious side effects. This is the first report of an AI used in primary prevention. Methods: NCIC CTG MAP.3 is a randomized trial designed to detect a 65% reduction in annual incidence of invasive breast cancer (IBC) on exemestane (E) versus placebo (P). Eligible postmenopausal women had ≥ one of the following risk factors: Gail score >1.66%, prior ADH, ALH, LCIS or DCIS with mastectomy, age over 60. Health-related and menopause-specific quality of life (QOL) were assessed by SF-36 and MENQOL questionnaires. Results: From 2004-2010, 4,560 women were randomized: age 62.5 yrs (37-90); Gail Score 2.3 % (0.6-21); BMI 28.0 kg/m2 (15.9-65.4). Risk factors included: age >60 yrs (49%); Gail score >1.66 (40%); and prior ADH, ALH, LCIS or DCIS with mastectomy (11%). At median follow-up of 35 months there were 11 IBCs on E and 32 on P (annual incidence 0.19% vs 0.55%; HR= 0.35, 95% CI 0.18-0.70, p = 0.002); ductal (10E/27P), lobular (1E/5P). Most tumors were ER positive (7E/27P); Her2/neu negative (10E/26P); TNM stage T1 (8E/28P), N0 (7E/22P), M0 (11E/30P). E was superior in all subgroups: by Gail score, age, BMI, prior LCIS and DCIS. The annual incidence rate of IBC or DCIS was 0.35% E and 0.77% P (HR=0.47;95% CI 0.27-0.79; p = 0.004) based on 64 IBCs or DCISs (20E/44P). Clinical bone fractures, osteoporosis, hypercholesterolemia or cardiovascular events were equal in both arms. No clinically meaningful differences in QOL were detected. Conclusions: Exemestane significantly reduced invasive and pre-invasive breast cancers in postmenopausal women at increased risk for breast cancer with no serious toxicities. Exemestane should be considered a new option for primary prevention of breast cancer. Supported by the Canadian Cancer Society; Pfizer Inc. PEG supported in part by Avon Foundation.