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Contains fulltext : 241226.pdf (Publisher’s version ) (Closed access) BACKGROUND: Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has previously been shown to extend progression-free survival versus placebo when given to patients with relapsed high-grade serous or endometrioid ovarian cancer who were platinum sensitive and who had a BRCA1 or BRCA2 (BRCA1/2) mutation, as part of the SOLO2/ENGOT-Ov21 trial. The aim of this final analysis is to investigate the effect of olaparib on overall survival. METHODS: This double-blind, randomised, placebo-controlled, phase 3 trial was done across 123 medical centres in 16 countries. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status at baseline of 0-1, had histologically confirmed, relapsed, high-grade serous or high-grade endometrioid ovarian cancer, including primary peritoneal or fallopian tube cancer, and had received two or more previous platinum regimens. Patients were randomly assigned (2:1) to receive olaparib tablets (300 mg in two 150 mg tablets twice daily) or matching placebo tablets using an interactive web or voice-response system. Stratification was by response to previous chemotherapy and length of platinum-free interval. Treatment assignment was masked to patients, treatment providers, and data assessors. The primary endpoint of progression-free survival has been reported previously. Overall survival was a key secondary endpoint and was analysed in all patients as randomly allocated. Safety was assessed in all patients who received at least one treatment dose. This trial is registered with ClinicalTrials.gov, NCT01874353, and is no longer recruiting patients. FINDINGS: Between Sept 3, 2013 and Nov 21, 2014, 295 patients were enrolled. Patients were randomly assigned to receive either olaparib (n=196 [66%]) or placebo (n=99 [34%]). One patient, randomised in error, did not receive olaparib. Median follow-up was 65·7 months (IQR 63·6-69·3) with olaparib and 64·5 months (63·4-68·7) with placebo. Median overall survival was 51·7 months (95% CI 41·5-59·1) with olaparib and 38·8 months (31·4-48·6) with placebo (hazard ratio 0·74 [95% CI 0·54-1·00]; p=0·054), unadjusted for the 38% of patients in the placebo group who received subsequent PARP inhibitor therapy. The most common grade 3 or worse treatment-emergent adverse event was anaemia (which occurred in 41 [21%] of 195 patients in the olaparib group and two [2%] of 99 patients in the placebo group). Serious treatment-emergent adverse events were reported in 50 (26%) of 195 patients receiving olaparib and eight (8%) of 99 patients receiving placebo. Treatment-emergent adverse events with a fatal outcome occurred in eight (4%) of the 195 patients receiving olaparib, six of which were judged to be treatment-related (attributed to myelodysplastic syndrome [n=3] and acute myeloid leukaemia [n=3]). INTERPRETATION: Olaparib provided a median overall survival benefit of 12·9 months compared with placebo in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation. Although statistical significance was not reached, these findings are arguably clinically meaningful and support the use of maintenance olaparib in these patients. FUNDING: AstraZeneca and Merck.

Background: There is limited prospective data for advanced breast cancer (ABC) patients (pts), both unresectable locally (ULABC) or metastatic (MBC) treated as per clinical practice. RegistEM study will provide epidemiological, pathological and clinical data, including treatments for different disease settings. Understanding the real distribution of BC subtypes is the primary objective. This is a non-interventional cohort study that will enroll around 1,867 pts (males or females) with ABC diagnosed from January 2016 to December 2019, either after recurrence or as first diagnosis, in 38 Spanish sites. Triple negative (TN) subtype histologically confirmed in the primary tumor (PT) and/or in a metastatic tumor lesion (M1) and recurrent disease from early stage, has been identified as an interesting group from a clinical perspective for detailed analysis. Methods: In this analysis, we describe the characteristics of 131 pts with TN subtype by local evaluation at any disease stage [in PT only (PT group), in M1 only (M1 group) and in both PT and M1 (group PT/M1)] until progressive disease (PD) at first-line and data of therapeutic options at second-line. Results: Distribution of 131 pts within the groups; PT, M1 and PT/M1, was 45.8%, 27.5% and 26.7%, respectively. To date, 32.1% pts have shown a change of subtype along their BC evolution, >50% of those changes was between TN and Luminal B HER2-. Median time from early BC (EBC) diagnosis until recurrent disease in terms of MBC or ULABC was 33.4 months (mo) (PT and PT/M1-26.0 mo; M1-60.2 mo), with the majority of pts recurring >12 mo (91.6%). Median age at diagnosis of ABC was 58 years (range 31-84), most pts were Caucasian (96.9%), female (99.2%) and postmenopausal (65.6%). Family history of BC and/or ovarian cancer was reported in 41.2% pts, a hereditary-risk genetic test was performed in 21.4% pts (8 pts with BRCA1/2 mutation). Lung (40.5%), lymph nodes (35.9%), bone (35.9%) and liver (20.6%) were the most frequent metastatic locations; central nervous system metastases were developed by 12.2% pts. The rate of visceral involment (60-70% pts) was similar among the 3 subgroups. The most frequent first-line therapies were chemotherapy (CT) (51.1%) and CT/biological therapy (BT) (32.8%). Most pts (68.7%) received CT in monotherapy (capecitabine 50%, taxanes 26.1%). Bevacizumab was the most frequent BT within the CT/BT combination (76.7%). Median duration of first line therapy was 4 mo (range 0.2-20.0). Progression to the first-line CT +/- bevacizumab was reported in 51.1% pts with a median time to progression (TTP) of 4.7 mo (range 0.8-19.0) in the whole group, being similar in pts with TN in and PT and PT/M1 (4.4 mo), and higher in pts with TN in M1 (7.1 mo), no statistically significant difference (p=0.38). A second-line therapy was reported in 57.3% pts and the most frequent therapies were CT (78.7%) (eribulin 33.9%, capecitabine 22.0%, platinum-based 22.0%) and CT/BT (12.0%) (CT-containing bevacizumab 77.8%). Median duration of second-line therapy was 3 mo (range 0.03-15.8) and PD has been reported in 80.0% pts. Third-line therapy was reported in 35.9% pts of this subset. Conclusion: In this subset of pts with TN ABC due to recurrent disease, lung, lymph nodes and bone are the most frequent metastatic locations. The main first- and second-line therapies were CT in monotherapy. Progression to the first-line conventional therapy (CT +/- bevacizumab) was reported in 51.1% pts with a median TTP of 4.7 mo (range 0.8-19.0) in the whole group, being similar in pts with TN in PT and PT/M1 (4.4 mo), and higher in pts with TN in M1 (7.1 mo), no statistically significant difference. 36% of the initial subset of pts reported to be treated in the third-line setting. Pts with TN only in M1 seem to have a longer time to progression from EBC. Citation Format: Carlos Jara, César A. Rodríguez, Isabel Alvarez, Catalina Falo, Purificación Martínez, Raquel Andrés, Josefina Cruz, Marta Mori, Encarna Adrover, Ariadna Tibau, Silvia Antolin, Mireia Margeli, Jose L. Alonso, Bella I. Pajares, M. Carmen Camara, J. Jose Miralles, Susana Bezares, Federico Rojo, Sara López-Tarruella, Angel Guerrero- Zotano. Geicam/2014-03 (RegisTEM): A prospective registry of unresectable locally advanced or metastatic breast cancer: Characteristics of a subset of patients with triple negative subtype [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 PS7-25.

Background: The RegistEM study is a non-interventional cohort study that will provide prospective data from >1,800 advanced breast cancer (ABC) patients (pts), either after recurrence or as first diagnosis in 38 Spanish sites. Primary objective is the distribution of BC subtypes. A new nomenclature has been proposed for those cases with immunohistochemistry (IHC) 1+ or 2+ and negative in situ hybridization (ISH), HER2-low BC. In clinical practice these tumors are reported as HER2 negative. This subpopulation has been identified as an interesting group from a clinical perspective. Methods: In this analysis (cut-off date 01/April/2020; database is ongoing) we describe the characteristics of 229 pts with hormone receptor (HR)+/HER2-low BC documented in a metastatic lesion after early disease recurrence and who received adjuvant endocrine therapy (ET). Three subgroups of pts have been considered for this analysis based on HER2 results: HER2 IHC 0, HER2-low, and HER2 ISH- (without IHC). Biological samples collection is part of study procedures. Results: The distribution of HER2 IHC 0, HER2-low, and HER2 ISH- subgroups was 52.4%, 42.8% and 4.8%, respectively. The median time to advance disease was 98.6, 88.8 and 106.9 mo in each group. Almost all pts were female and Caucasian (99%), and at ABC diagnosis, 75.5% were postmenopausal. Median age was 59 years (range 33-88). Fourteen (6.1%) pts had HER2+ (IHC 3+ or ISH amplified) BC subtype during their disease. Family history of BC and/or ovarian cancer was reported in 31.4% pts, an hereditary-risk genetic test was performed in 11.4% (n=26) pts in total and BRCA2 gene mutation (n=6) was the only one reported. The most frequent metastases are included in Table 1. Visceral disease was present in 63.3% pts and 76% pts had ≤2 locations. The most frequent 1st-line therapies were ET/biological therapy (BT) (46.7%) and ET (28.8%), and were equal distributed in the 3 subgroups. The most common ET/BT regimens were aromatase inhibitor (AI)/cyclin-dependent kinase 4/6 inhibitor (CDKi) (49.1%/48.9%/42.9% in each subgroup) and fulvestrant (FUL)/CDKi (35.8%/27.7%/28.6%); AIs (50%/64%/66.7%) and FUL (31.6%/20%/0%) were also the most common drugs for monotherapy ET. A 2nd-line therapy was reported in ~53% pts in HER2 IHC 0 and HER2-low, and in 36% pts in HER2 ISH-. The median time to progression (TTP) to 1st-line therapy was 11.4 mo (1.2-37.0), being similar in pts with HER2 IHC 0 and HER2-low (~11 mo), and higher in pts with HER2 ISH- (16 mo). The most frequent 2nd-line therapies were ET/BT (~34% in HER2 IHC 0 and HER2-low, and 25% in HER2 ISH-) [FUL/CDKi (36.4%/47.1%/100%), AI/CDKi (36.4%/23.5%/0%)], chemotherapy as monotherapy (17 pts out of 63 in HER2 IHC 0, 17 pts out of 53 in HER2-low and 1 pt (capecitabine) out of 4 in HER2 FISH-) (capecitabine 29.4%/52.9% in HER2 IHC 0 and HER2-low). Median duration of 2nd-line therapy was ~5 mo in HER2 IHC 0 and ~8 mo in HER2-low and HER2 ISH-; disease progression was reported in 52.4%/62.3%/50% pts, respectively. Conclusions: In this population of HR+ tumors, the proportion of HER2 IHC 0 and HER2-low groups was similar. Time to advance relapse and the distribution of distant metastases were similar among the groups. The most common first- and second-line therapy was the ET/BT combination, with AI/CDKi and FUL/CDKi, respectively. Table 1Location of metastatic lesionsIHC 0HER2-lowISH- non IHCN=120 N (%)N=98 N (%)N=11 N (%)Bone74 (61.7)55 (56.1)6 (54.5)Liver36 (30.0)37 (37.8)3 (27.3)Lung27 (22.5)21 (21.4)5 (45.5)Lymph Node27 (22.5)21 (21.4)2 (18.2)Soft Tissue6 (5.0)11 (11.2)0CNS3 (2.5)4 (4.1)0Other43 (35.8)31 (31.6)5 (45.5) Citation Format: Isabel Álvarez, Angel Guerrero, Sara López-Tarruella, Purificación Martínez, Marta Mori, Catalina Falo, Silvia Antolín, César A Rodríguez, Mireia Margeli, Isabel Garau, Ariadna Tibau, Diana Moreno, Josefina Cruz, María José Echarri, Antonio Antón, Álvaro Rodríguez-Lescure, María José Escudero, Susana Bezares, Federico Rojo, Carlos Jara. Characteristics of HR+/HER2- patients with recurrent disease by HER2 expression from a prospective registry of unresectable locally advanced or metastatic breast cancer: GEICAM/2014-03 (RegistEM) [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 PS7-24.

Background: The RegistEM study will provide prospective data from advanced breast cancer (ABC) patients (pts). Understanding the real distribution of BC subtypes is its primary objective. A new nomenclature has been proposed for those cases with HER2 1+ or 2+ by immunohistochemistry and negative in situ hybridization, HER2-low BC. In clinical practice, these tumors are reported as HER2 negative. Methods: This is a non-interventional study that will enroll approximately 1,867 pts with ABC diagnosed from January 2016 to December 2019, either after recurrence or as 1st diagnosis, in 38 Spanish sites. Biological samples (primary and/or metastatic tumor lesions, and blood) collection is part of its procedures. In this analysis (cut-off date 01/April/2020, database ongoing), we describe the characteristics of pts with Triple Negative (TN) subtype and HER2-low expression (as mentioned above). Biomarkers, including HER2, were determined in either primary tumor (PT), M1 or in both, PT and M1. Results: This subset of pts make up 37.4% (n=49) of TN pts considered for this analysis (n=131). Their distribution within the three groups (PT, M1 and PT/M1), was 46.9% (n=23), 42.9% (n=21) and 10.2% (n=5), respectively. These pts were diagnosed with early BC (EBC) and at recurrence, 91.7% presented distant metastases. Median time from EBC diagnosis until recurrent disease in terms of ABC was 29.8 months (mo), with the majority of pts recurring at >12 mo (95.9%), similar to the whole TN subset. Most pts were Caucasian (98%), and at diagnosis of ABC, the median age was 60 years (range 31-84) and 65.3% were postmenopausal. A change of BC subtype was documented in 15/49 (30.6%) pts, with the higher rate in M1 group (52.4%); as opposed to the TN subset, a change to HER2+ disease was reported in 6/15 (40.0%) pts and just after the TN subtype in all cases. Family history of BC and/or ovarian cancer was reported in 42.9% pts and any genetic test to assess the hereditary risk was performed in 30.6% pts. Similarly to TN subset, lung (36.7%), lymph nodes and bone (34.7% each) and liver (24.5%) were the most frequent metastatic locations; central nervous system metastases were developed by 14.3% pts. Visceral involvement was present in 66.7% pts, being this rate lower in M1 compared to PT and PT/M1 groups. The most frequent 1st-line therapies were chemotherapy (CT) (44.9%) and CT/biological therapy (BT) (36.7%). Type of CT mainly included capecitabine (36.4%), taxanes (27.3%), eribulin (13.6%) and platinum-based combinations (13.6%). Most pts received CT as monotherapy (86.4%). Bevacizumab (BVZ) was the most frequent BT associated to CT (77.8%), mainly with capecitabine and/or paclitaxel (72.2%). Progressive disease to 1st-line therapy in the whole group was reported in 73.5% pts (higher than in TN subset), with a median time to progression (TTP) of 5.7 mo (range 1.7-15.0); PT was the group with a higher PD rate. A 2nd-line therapy was reported in 63.3% pts. Similarly to 1st-line setting, the most frequent 2nd-line therapies were CT (74.2%) and CT/BT (12.9%) (with BVZ in 75.0% pts). CT in monotherapy was reported in 69.6% pts (capecitabine 31.3%, eribulin 25.0%). Median duration of this line therapy was 3.0 mo (range 0.6-15.8), PD has been reported in 96.8% pts (similar between groups), and 3rd-line therapy in 25/49 (51.0%) pts. Conclusions: In TN/HER2-low ABC pts, lung, lymph nodes and bone were the most frequent metastatic locations. As opposed to TN subset, HER2+ disease is part of the subtype changes reported. Although the main 1st- and 2nd-line therapies were CT and CT/BT, similarly to TN subset, the rate of pts with PD to 1st- and 2nd-line therapies is higher, and also those pts treated in the 3rd-line setting. Citation Format: Carlos Jara, Isabel Álvarez, César A Rodríguez, Purificación Martínez, Raquel Andrés, Álvaro Rodríguez-Lescure, Diego Malón, Jose Luis Alonso, Encarna Adrover, María José Echarri, Mireia Margeli, Ariadna Tibau, Judith Ramírez, Silvia Antolín, Ruth Campo, Juan José Miralles, Susana Bezares, Federico Rojo, Sara López-Tarruella, Angel Guerrero-Zotano. Geicam/2014-03 (registem): A prospective registry of advanced breast cancer: A subset of triple negative breast cancer patients with her2 low expression [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 PS7-35.

Summary Background Increasing cancer drug prices are a challenge for patients and health systems in the USA and Europe. By contrast with the USA, national authorities in European countries often directly negotiate drug prices with manufacturers. The American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) developed frameworks to evaluate the clinical value of cancer therapies: the ASCO-Value Framework (ASCO-VF) and the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). We aimed to assess the association between the clinical benefit of approved cancer drugs based on these frameworks and their drug prices in the USA and four European countries (England, Switzerland, Germany, and France). Methods For this cost–benefit analysis, we identified all new drugs with initial indications for adult cancers that were approved by the US Food and Drug Administration between Jan 1, 2009, and Dec 31, 2017, and by the European Medicines Agency up until Sept 1, 2019. For drugs indicated for solid tumours, we assessed clinical benefit using ASCO-VF and ESMO-MCBS. We compared monthly drug treatment costs between benefit levels using hierarchical linear regression models, and calculated Spearman's correlation coefficients between costs and benefit levels for individual countries. Findings Our cohort included 65 drugs: 47 (72%) drugs were approved for solid tumours and 18 (28%) were approved for haematological malignancies. The monthly drug treatment costs in the USA were a median of 2·31 times (IQR 1·79–3·17) as high as in the assessed European countries. There were no significant associations between monthly treatment costs for solid tumours and clinical benefit in all assessed countries, using the ESMO-MCBS (p=0·16 for the USA, p=0·98 for England, p=0·54 for Switzerland, p=0·52 for Germany, and p=0·40 for France), and for all assessed countries except France using ASCO-VF (p=0·56 for the USA, p=0·47 for England, p=0·26 for Switzerland, p=0·23 for Germany, and p=0·037 for France). Interpretation Cancer drugs with low or uncertain clinical benefit might be prioritised for price negotiations. Value frameworks could help identify therapies providing high clinical benefit that should be made rapidly available across countries. Funding Swiss Cancer Research Foundation (Krebsforschung Schweiz).

Purpose: This phase II study determined the efficacy of lacnotuzumab added to gemcitabine plus carboplatin (gem-carbo) in patients with advanced triple-negative breast cancer (TNBC). Patients and Methods: Female patients with advanced TNBC, with high levels of tumor-associated macrophages not amenable to curative treatment by surgery or radiotherapy were enrolled. Lacnotuzumab was dosed at 10 mg/kg every 3 weeks, ± a dose on cycle 1, day 8. Gemcitabine (1,000 mg/m2) and carboplatin (dose in mg calculated by area under the curve [mg/mL/min] × (glomerular filtration rate [mL/min] + 25 [mL/min]) were dosed every 3 weeks. Treatment continued until unacceptable toxicity, disease progression, or discontinuation by physician/patient. Results: Patients received lacnotuzumab + gem-carbo (n = 34) or gem-carbo (n = 15). Enrollment was halted due to recruitment challenges owing to rapid evolution of the therapeutic landscape; formal hypothesis testing of the primary endpoint was therefore not performed. Median progression-free survival was 5.6 months [90% confidence interval (CI), 4.47–8.64] in the lacnotuzumab + gem-carbo arm and 5.5 months (90% CI, 3.45–7.46) in the gem-carbo arm. Hematologic adverse events were common in both treatment arms; however, patients treated with lacnotuzumab experienced more frequent aspartate aminotransferase, alanine aminotransferase, and creatine kinase elevations. Pharmacokinetic results showed that free lacnotuzumab at 10 mg/kg exhibited a typical IgG pharmacokinetic profile and target engagement of circulating colony-stimulating factor 1 ligand. Conclusions: Despite successful target engagement and anticipated pharmacokinetic profile, lacnotuzumab + gem-carbo showed comparable antitumor activity to gem-carbo alone, with slightly poorer tolerability. However, the data presented in this article would be informative for future studies testing agents targeting the CSF1–CSF1 receptor pathway in TNBC.

Background The clinical benefit and pricing of breakthrough-designated cancer drugs are uncertain. This study compares the magnitude of the clinical benefit and monthly price of new and supplemental breakthrough-designated and non-breakthrough-designated cancer drug approvals. Methods A cross-sectional cohort comprised approvals of cancer drugs for solid tumors from July 2012 to December 2017. For each indication, the clinical benefit from the pivotal trials was scored via validated frameworks: the American Society of Clinical Oncology Value Framework (ASCO-VF), the American Society of Clinical Oncology Cancer Research Committee (ASCO-CRC), the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS), and the National Comprehensive Cancer Network (NCCN) Evidence Blocks. A high clinical benefit was defined as scores ≥ 45 for the ASCO-VF, overall survival gains ≥ 2.5 months or progression-free survival gains ≥ 3 months for all cancer types for the ASCO-CRC criteria, a grade of A or B for trials of curative intent and a grade of 4 or 5 for trials of noncurative intent for the ESMO-MCBS, and scores of 4 and 5 and a combined score ≥ 16 for the NCCN Evidence Blocks. Monthly Medicare drug prices were calculated with Medicare prices and DrugAbacus. Results This study identified 106 trials supporting approval of 52 drugs for 96 indications. Forty percent of these indications received the breakthrough designation. Among the included trials, 33 (43%), 46 (73%), 35 (34%), and 67 (69%) met the thresholds established by the ASCO-VF, ASCO-CRC, ESMO-MCBS, and NCCN, respectively. In the metastatic setting, there were higher odds of clinically meaningful grades in trials supporting breakthrough drugs with the ASCO-VF (odds ratio [OR], 3.69; P = .022) and the NCCN Evidence Blocks (OR, 5.80; P = .003) but not with the ASCO-CRC (OR, 3.54; P = .11) or version 1.1 (v1.1) of the ESMO-MCBS (OR, 1.22; P = .70). The median costs of breakthrough therapy drugs were significantly higher than those of nonbreakthrough therapies (P = .001). Conclusions In advanced solid cancers, drugs that received the breakthrough therapy designation were more likely than nonbreakthrough therapy drugs to be scored as providing a high clinical benefit with the ASCO-VF and the NCCN Evidence Blocks but not with the ESMO-MCBS v1.1 or the ASCO-CRC scale.

Background: There is limited prospective data for advanced breast cancer (ABC) patients (pts), unresectable locally or metastatic, treated as per clinical practice. RegistEM, an academic study conducted by a non-profit collaborative group, will provide epidemiological, pathological and clinical data as per routine practice, including treatments for different disease settings, collected from pts’ medical records. Understanding the real distribution of BC subtypes is the primary objective. This is a non-interventional cohort study that will enroll approximately 1,867 pts with advanced disease diagnosed from January 2016 to December 2019, either after recurrence or as first diagnosis (de novo), in 38 Spanish sites representative of the whole country geography and whose investigators are GEICAM members. Biological samples (primary and/or metastatic tumor tissue, and blood) collection is part of study procedures. Methods: In this analysis we describe the characteristics of 229 pts with HR+/HER2- BC documented in a metastatic tumor lesion after disease recurrence and who received adjuvant endocrine therapy (ET). This subpopulation has been identify as an interesting group from a clinical perspective for detailed analysis. Three subgroups of pts have been considered for this analysis based on their disease-free interval (DFI) since the diagnosis of early disease: 50% pts recurring at ≥84 mo and only 1.3% pts at ≤12 mo. Most pts were Caucasian (99.1%) and female (99.6%), and at ABC diagnosis, 75.5% were postmenopausal and their median age was 59 years (33-88); median age was higher in pts with DFI ≥60 mo. Family history of BC and/or ovarian cancer was reported in 31.4% pts, with a slightly higher percentage in pts with DFI 50% pts recurred at ≥84 mo. Bone is the most frequent metastatic location in all DFI subgroups. The most common 1st- and 2nd-line therapies were the ET/BT combination, with AI/CDKi and FUL/CDKi, respectively. The median TTP to 1st-line therapy was superior in pts with DFI ≥60 mo. Citation Format: Isabel Alvarez, Angel Guerrero- Zotano, Sara López-Tarruella, Purificación Martínez, Marta Mori, Catalina Falo, Silvia Antolin, Cesar A. Rodríguez, Mireia Margeli, Isabel Garau, Ariadna Tibau, Diana Moreno, Josefina Cruz, M. Jose Echarri, Juan Lao, Alvaro Rodríguez-Lescure, Juan Jose Miralles, Susana Bezares, Federico Rojo, Carlos Jara. Characteristics of HR+/HER2- patients with recurrent disease from a prospective registry of unresectable locally advanced or metastatic breast cancer: GEICAM/2014-03 (RegistEM) [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 PS7-08.

Historically, patient experience, including symptomatic toxicities, physical function, and disease-related symptoms during treatment or their perspectives on clinical trials, has played a secondary role in cancer drug development. Regulatory criteria for drug approval require that drugs are safe and effective, and almost all drug approvals have been based only on efficacy endpoints rather than on quality-of-life (QoL) assessments. In contrast to Europe, information regarding the impact of drugs on patients’ QoL is rarely included in oncology drug labeling in the United States. Until recently, patient input and preferences have not been incorporated into the design and conduct of clinical trials. In recent years, a more in-depth understanding of cancer biology, as well as regulatory changes focused on expediting cancer drug development and approval, has allowed earlier access to novel therapeutic agents. Understanding the implications of these expedited programs is important for oncologists and patients, given the rapid expansion of these programs. In this article, we provide an overview of the role of QoL in the regulatory drug–approval process, key issues regarding trial participation from the patient perspective, and the implications of key expedited approval programs that are increasingly being used by regulatory bodies for cancer care.

1086 Background: The impact of the interval of radiological assessment on the magnitude of benefit observed in randomized trials (RCTs) in metastatic breast cancer is undefined. Methods: All RCTs investigating anti-neoplastic drugs for metastatic breast cancer published between 2006 and 2019 were identified. Intervals for restaging were categorized as short ( < 9 weeks) or long (≥9 weeks). Hazard ratios (HRs) and 95% confidence intervals for progression-free survival (PFS) and overall-survival (OS) were pooled in a meta-analysis and compared between trials employing short and long restaging intervals assessed as subgroup analyses. Analyses were repeated for pre-specified subgroups according to disease subtype, drug type, whether experimental therapy was added to or replaced standard treatment and whether HR for PFS was < 1 or ≥1. Results: Eighty-nine studies comprising 95 comparisons and 44,901 patients were included. The magnitude of PFS benefit was non-significantly larger in trials which employed short compared to long restaging intervals (HR 0.79 vs. 0.86, p = 0.15). Short restaging interval was associated with significantly higher magnitude of effect on PFS in pre-specified subgroups including non-first line studies (HR 0.78 vs. 0.92, p = 0.04), studies with drugs replacing standard treatment (HR 0.86 vs. 1.04, p = 0.02) and studies performed exclusively in human epidermal growth factor receptor 2 (HER2) positive disease (HR 0.72 vs. 0.90, p = 0.02). Restaging interval was not associated with OS for all included studies (HR 0.92 vs. 0.93, p = 0.66) or for any of the pre-specified subgroups. Conclusions: Shorter restaging intervals are associated with a higher magnitude of effect of PFS, but not OS. Awareness of the impact of the restaging interval on quantification of intermediate endpoints such as PFS is important for the design and interpretation of RCTs.

6571 Background: The American Society of Clinical Oncology Cancer Research Committee (ASCO-CRC), the ASCO Value Framework Net Health Benefit score version 2 (ASCO-VF), and the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS) are validated tools quantifying the clinical benefit for cancer drugs. Here, we assess the overall survival (OS), quality of life (QoL) and magnitude of clinical benefit of trials supporting breast cancer drug approval by the US Food and Drug Administration (FDA) in the last 25 years. Methods: We searched Drugs@FDA website for all breast cancer drug approvals from January 1, 1995 to December 30, 2020. Drug labels and reports of registration trials were reviewed. We collected data on trial characteristics, efficacy, toxicity and QoL. When more than one study supported a single indication, we preferred efficacy-oriented endpoints (typically OS) to QoL. We excluded trials supporting accelerated-approval indications if these were converted to regular approval during the study period. We scored clinical benefit using the ASCO-CRC in palliative setting, and ASCO-VF and ESMO-MCBS in both curative and palliative setting. Substantial clinical benefit was defined as: OS gains ≥2.5 months and progression-free survival gains ≥ 3 months for ASCO-CRC criteria; ASCO-VF scores ≥ 45 and grade of A or B for trials of curative intent and 4 or 5 for those of non-curative intent using ESMO-MCBS. Trends over time were assessed using Chi-squared test for trend. Results: We identified 51 trials supporting the approval of 32 individual drugs for 51 indications; 12 (24%) were in the curative setting and 39 (76%) in the palliative setting. At the time of approval, 8 (16%) trials reported significant improvement in OS. QoL was reported in 22 trials (43%). Among these, 8 (36%) showed improvement in QoL. For curative intent, we applied ASCO-VF and ESMO-MCBS score to 11 (92%) trials, finding clinical benefit in 10 (91%) and 2 (18%) trials, respectively. In the palliative setting, we used ASCO-CRC, ASCO-VF and ESMO-MCBS scores to rate 32 (82%), 33 (85%) and 38 (97%) trials. Substantial clinical benefit was observed in 20 (63%), 12 (36%) and 7 (19%) trials, respectively. Over time, there has been a decrease in the number of trials supporting approval based on OS (1996-2003 50% vs 2004-12 38% vs 2013-20 13%, P trend = 0.033). There were no statistically significant changes over time in QoL, ASCO-CRC, ASCO-VF and ESMO-MCBS scores. Conclusions: For palliative intent, most trials supporting FDA approval of breast cancer drugs do not meet the ASCO-VF or ESMO-MCBS criteria for substantial clinical benefit. There is substantial inter-framework variability in the assessment of clinical benefit in the curative setting. Over time, there has been a substantial shift towards use of surrogate endpoints as the basis for approval without a clear improvement in substantial clinical benefit.

National Comprehensive Cancer Network (NCCN) guidelines can include recommendations for off-label use of anti-cancer drugs. Here, we evaluate NCCN recommendations not supported by US Food and Drug Administration (FDA) approval and explore associations with such recommendations.All NCCN recommendations for MBC and their supporting data were identified. Drug labels were reviewed to determine whether recommendations are FDA approved. Logistic regression was used to compare FDA approved and off-label recommendations for pre-specified categories, including drug type, tumor subtype, level of recommendation and line of therapy.Of 124 recommendations identified, 68 (55%) were off-label. Chemotherapy and human epidermal growth factor receptor 2 (HER2) targeted drugs were associated with lower odds of FDA approval (OR = 0.28, p = 0.001 and OR = 0.29, 95% p = 0.005, respectively). Recommendations for endocrine therapy (OR = 3.44, p = 0.009) and non-HER2 targeted treatment (OR = 10.0, p 0.001) were more commonly FDA approved indications. Compared to combination therapies, monotherapies were more likely to be FDA approved (OR = 3.45, p = 0.001) as were category 1 (OR = 7.63, p = 0.001) and preferred NCCN recommendations (OR = 4.07, p 0.001). Compared to off-label recommendations, NCCN recommendations of approved drugs were based on significantly higher sample size (mean 477 vs. 342 patients, p = 0.02) and were non-significantly associated with availability of randomized data (OR = 2.0, 95% CI 0.89-4.49, p = 0.09).More than half of all NCCN recommendations for MBC are off-label, mostly involving chemotherapy containing regimes for HER2 negative disease and combinations which include HER2-targeted drugs. Improved transparency of NCCN guidelines may result from reporting of the strength of the evidence supporting recommendations for MBC.

1582 Background: Despite the use of clinical eligibility criteria and mutation predictive models, a great proportion of families are negative for germline mutations in BRCA1/2 genes. Traditionally, risk assessment of inconclusive results included the recommendation of high-risk surveillance protocol, the update of incident cancer cases in the family and the consideration of additional testing to rule out the possibility of phenocopy. More recently, next generation sequencing multigene panels have become a standard practice in cancer genetics clinics worldwide. We addressed the value of multigene panel retesting of BRCA1/2 negative HBOC families in our institution. Methods: After genetic counseling session and informed consent, a total of 137 individuals (119 probands and 18 extra cancer-affected relatives) from distinct BRCA1/2 negative families were retested using a panel containing 11 breast and ovarian cancer susceptibility genes ( BRCA1/2, PALB2, ATM, CHEK2, PTEN, TP53, STK11, BRIP1, RAD51C, RAD51D). Results: According to the BOADICEA model, the remaining probability of mutation in BRCA1/2 or PALB2 genes in our cohort was 5.5% (0.1-61). The reasons for considering retesting were the addition of any incident cancer diagnosis in 33 cases (24%), a prior study with a low sensitivity screening technique (dHPLC) in 6 families (5%) and the expansion of the study to other putative breast and ovarian susceptibility genes in 98 families (71%). Overall, 3 pathogenic (2 BRCA2, 1 CHEK2) and 8 likely pathogenic variants (1 BRCA2, 4 CHEK2 and 3 ATM) were found. The prevalence was 8%. The detection rate among 19 families with a > 10% remaining probability of mutation in BRCA1/2 and PALB2 genes was 26%. The 3 clinically significant variants in BRCA2 were detected in 2 families and 1 updated cancer family history (BOADICEA remaining probability of 59, 61 and 12%, respectively). Cascade testing was subsequently done in 15 relatives resulting 8 in mutation carriers and 9 true negatives. Conclusions: Our results support the value of updating cancer incident cases and considering expanded panels in selected families.

Background Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, has previously shown efficacy in a phase 2 study when given in capsule formulation to all-comer patients with platinum-sensitive, relapsed high-grade serous ovarian cancer. We aimed to confirm these findings in patients with a BRCA1 or BRCA2 (BRCA1/2) mutation using a tablet formulation of olaparib. Methods This international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial evaluated olaparib tablet maintenance treatment in platinum-sensitive, relapsed ovarian cancer patients with a BRCA1/2 mutation who had received at least two lines of previous chemotherapy. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status at baseline of 0–1 and histologically confirmed, relapsed, high-grade serous ovarian cancer or high-grade endometrioid cancer, including primary peritoneal or fallopian tube cancer. Patients were randomly assigned 2:1 to olaparib (300 mg in two 150 mg tablets, twice daily) or matching placebo tablets using an interactive voice and web response system. Randomisation was stratified by response to previous platinum chemotherapy (complete vs partial) and length of platinum-free interval (6–12 months vs ≥12 months) and treatment assignment was masked for patients, those giving the interventions, data collectors, and data analysers. The primary endpoint was investigator-assessed progression-free survival and we report the primary analysis from this ongoing study. The efficacy analyses were done on the intention-to-treat population; safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01874353, and is ongoing and no longer recruiting patients. Findings Between Sept 3, 2013, and Nov 21, 2014, we enrolled 295 eligible patients who were randomly assigned to receive olaparib (n=196) or placebo (n=99). One patient in the olaparib group was randomised in error and did not receive study treatment. Investigator-assessed median progression-free survival was significantly longer with olaparib (19·1 months [95% CI 16·3–25·7]) than with placebo (5·5 months [5·2–5·8]; hazard ratio [HR] 0·30 [95% CI 0·22–0·41], p

Background Given rising cancer drug costs, US Medicare recently proposed to tie some drug prices to average prices paid by comparable countries. To understand the potential scope of this policy, we assessed differences in cancer drug prices in the US and European countries. We also evaluated the correlation between drug prices and their clinical benefit, as measured by two value frameworks: the American Society of Clinical Oncology Value Framework v2 (ASCO VF) and the European Society for Medical Oncology Magnitude of Clinical Benefit Scale v1.1 (ESMO-MCBS). Methods We identified all new drugs for adult solid and hematologic cancers, approved by the FDA from 2009-2017 and that have also been approved by the EMA by December 31, 2018. US average sales prices (and if not available, wholesale acquisition costs) were extracted as of February 1, 2019, and compared to comparable currency-adjusted ex-factory drug costs in England, France, Germany, and Switzerland. ASCO VF and ESMO-MCBS scores were assessed for pivotal trials supporting solid tumor drugs; in case of multiple trials, we focused on the highest score. Consistent with the developers of the rating scales, “high benefit” was defined as scores of A-B (neo/adjuvant setting) and 4-5 (palliative setting) on the ESMO-MCBS scale and scores ≥45 on the ASCO VF. Linear regression models and non-parametric Kruskal-Wallis test and were used to assess the association between drug prices and benefit scores. Results The study cohort included 63 drugs approved by the FDA and the EMA during the study period. 46 (73%) were approved for solid tumors, and 17 (27%) were approved for hematologic malignancies. Overall, median cancer drug prices in Europe were 52% (interquartile range: 37-72%) lower than US prices. There was no association between monthly treatment cost and ASCO-VF or ESMO-MCBS scores in any country. There was also no association between price differential between US and median European drug prices and either ASCO-VF (P = 0.599) or ESMO-MBCS (P = 0.321) scores. Conclusions Drug prices of cancer drugs were not associated with clinical benefit in the US or in European countries. Cancer drug prices in the US were significantly higher than in the compared European countries. Legal entity responsible for the study University of Zurich. Funding Swiss Cancer League. Disclosure All authors have declared no conflicts of interest.

1077 Background: In Spain there is limited prospective data for unresectable locally advanced breast cancer (ULABC) or metastatic breast cancer (MBC) patients (pts) treated as per clinical practice. RegistEM study will provide epidemiological, pathological and clinical data, including treatments given for different disease stages. Understanding the real distribution of the different BC subtypes is the primary objective. Methods: This is a non-interventional cohort study enrolling approximately 1,400 pts with advanced disease diagnosed from January 2016 to December 2018, either after recurrence or as first diagnosis, in 38 Spanish sites. Biological samples (primary tumor, metastatic lesions, blood) are currently being collected. In this first analysis, we include 489 pts who met study criteria before October 31, 2017. All data are described in two subgroups: on the most recent tumor lesion or on the primary breast tumor. Results: At first diagnosis, 67.9%, 31.5% and 0.6% of pts had early BC (EBC), MBC and ULABC, respectively. In the total analysis population, median age at diagnosis of advanced disease was 59.6 years, most of pts were white (98.2%), female (99.4%) and postmenopausal (70%). Family history of BC and ovarian cancer was reported in 5.7% pts. In ~390 pts BC clinical subtypes distribution was luminal B(HER2-)-like (~55%), luminal B(HER2+)-like (~16%), luminal A-like or triple negative (TN) (~10% each) and HER2 enriched-like (~8%). Median time to recurrence (years) in EBC pts was: luminal A-like 5.8, luminal B(HER2-)-like 5.1, luminal B(HER2+)-like 3.9, HER2 enriched-like 2.7 and TN 1.7. Bone (59%), visceral (58%) and lymph node (27%) lesions were the most frequent metastatic locations. The two most frequent therapies in first line consisted in: endocrine therapy (ET) (47%) and ET+biological therapy (BT) (29%) for luminal A-like; ET (32%) and ET+BT (32%) for luminal B(HER2-)-like; chemotherapy (CT)+ET+BT (43%) and CT+BT (24%) for luminal B(HER2+)-like; CT+BT (68%) and CT (16%) for HER2 enriched-like; CT (59%) and CT+BT (34%) for TN. Conclusions: These first data confirm that luminal B (HER2-)-like subtype is the most predominant in MBC.

This study matches entries in ClinicalTrials.gov for cancer drug trials at initiation of the trial with later entries and with journal reports of the trials to assess modifications in trial design, external factors associated with such modifications, and transparency in reporting them.

Background: Src is a non-receptor tyrosine kinase involved in signalling and crosstalk between growth-promoting pathways. We aim to investigate the relationship of active Src in response to trastuzumab of HER2-positive breast carcinomas. Methods: We selected 278 HER2-positive breast cancer patients with (n = 154) and without (n = 124) trastuzumab treatment. We performed immunohistochemistry on paraffin-embedded tissue microarrays of active Src and several proteins involved in the PI3K/Akt/mTOR pathway, PIK3CA mutational analysis and in vitro studies (SKBR3 and BT474 cancer cells). The results were correlated with clinicopathological factors and patients' outcome. Results: Increased pSrc-Y416 was demonstrated in trastuzumab-resistant cells and in 37.8% of tumours that correlated positively with tumour size, necrosis, mitosis, metastasis to the central nervous system, p53 overexpression and MAPK activation but inversely with EGFR and p27. Univariate analyses showed an association of increased active Src with shorter survival in patients at early stage with HER2/hormone receptor-negative tumours treated with trastuzumab. Conclusions: Src activation participates in trastuzumab mechanisms of resistance and indicates poor prognosis, mainly in HER2/hormone receptor-negative breast cancer. Therefore, blocking this axis may be beneficial in those patients.

Background Hormone receptor positive breast cancer is characterized by the potential for disease recurrence many years after initial diagnosis. Endocrine therapy has been shown to reduce the risk of such recurrence, but the optimal duration of endocrine therapy remains unclear. Methods We conducted a systematic review and meta-analysis to quantify the benefits and harms of extended adjuvant tamoxifen (>5 years of therapy) compared with adjuvant tamoxifen (5 years of therapy). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for disease recurrence, death and adverse events. Subgroup analyses by timing of recurrence and baseline lymph node and menopause status were carried. Results Five trials comprising 21,554 patients were included. Extended adjuvant tamoxifen was not associated with a significant reduction in the risk of recurrence (OR:0.89, 95% CI 0.76–1.05, p = 0.17). There was no association between extended adjuvant tamoxifen and all-cause death (OR:0.99, 95% CI 0.84–1.16, p = 0.88). There was an apparent reduction in risk of recurrence occurring after completion of extended adjuvant tamoxifen with little evidence of effect during therapy, however, this difference was not significant (p for difference 0.10). Subgroup analysis suggested that a greater effect size among lymph node positive patients compared with those who are lymph node negative (NNT: 25 vs. 49). There was no apparent difference in the effect between pre- and post-menopausal patients. Endometrial carcinoma was substantially more frequent with extended adjuvant tamoxifen (OR:2.06, 95% CI 1.65–2.58, p

Obesity, associated with inflammation, has been linked to poor prognosis in breast cancer. Research investigating the potential role of C-reactive protein (CRP), an obesity-associated systemic marker of inflammation, as a mediator of adverse prognostic effects of obesity has yielded inconsistent results. We examined the association of highly sensitive CRP (hsCRP) with obesity-related factors and breast cancer outcome. A cohort of 535 non-diabetic women diagnosed with T1-3, N0-1, M0 breast cancer, was assembled between 1989 and 1996 and followed prospectively. Circulating levels of hsCRP were analyzed on blood obtained postoperatively, prior to systemic therapy, in 501 women. Correlations and prognostic associations were analyzed using one-way analysis of variance, Spearman’s rank correlation coefficients (r) and Cox models. hsCRP was significantly correlated with body mass index (r = 0.60), insulin (r = 0.44), leptin (r = 0.54), and lipids, but not T or N stage, grade or estrogen receptor/progesterone receptor. At a median follow-up of 12 years, hsCRP was not associated with distant disease-free survival or overall survival in univariable [Q4 vs. Q1 hazard ratio (HR) 1.03, 95 % confidence interval (CI) 0.69–1.52, P = 0.9 and HR 1.27, 95 % CI 0.86–1.86, P = 0.24, respectively] or multivariable [Q4 vs Q1 HR 1.02, 95 % CI 0.66–1.59, P = 0.93 and HR 1.17, 95 % CI 0.76–1.81, P = 0.48 respectively] analyses. hsCRP was associated with age, comorbidities, and the insulin resistance syndrome but not with breast cancer outcome.

539 Background: Hormone receptor positive breast cancer is characterized by the potential for disease recurrence many years after initial diagnosis. Endocrine therapy has been shown to reduce the risk of such recurrence, but the optimal duration of endocrine therapy remains unclear. Methods: We conducted a systematic review and meta-analysis to quantify the relative and absolute benefits and harms of extended adjuvant tamoxifen (>5 years of therapy) compared with adjuvant tamoxifen (≤5 years of therapy). Odds ratios (ORs), 95% confidence intervals (CIs), absolute risks, and the number needed to treat (NNT) were computed for pre-specified events including disease recurrence, distant recurrence, all-cause death, endometrial carcinoma, cardiovascular death and treatment discontinuation. Subgroup analyses by timing of recurrence and baseline lymph node and menopause status were carried out. Results: Six trials comprising 25,326 patients were included. Extended adjuvant tamoxifen was associated with a non-significant reduction in the risk of recurrence (OR 0.89, 95% CI 0.77-1.04, p=0.14, NNT 74). Similar results were seen for distant recurrence (OR 0.88, 95% CI 0.75-1.04, p=0.14, NNT 70). There was no association between extended adjuvant tamoxifen and all-cause death (OR 1.06, 95% CI 0.86-1.31, p=0.58). There was no reduction in risk during extended adjuvant therapy (i.e. between years 5 and 9), but a potential reduction in the risk of recurrence after completion of extended adjuvant tamoxifen (i.e. beyond 10 years after diagnosis). Subgroup analysis suggested benefit in lymph node positive patients. Endometrial carcinoma was substantially more frequent with extended adjuvant tamoxifen (OR 1.81, 95% CI 1.45-2.25, p

550 Background: Obesity, commonly associated with inflammation, is associated with poor prognosis in BC. Previous research suggests CRP, an obesity-associated marker of systemic inflammation, may mediate the adverse prognostic effects of obesity and be associated with fatigue. We examined the association of hsCRP with obesity-related factors, fatigue and distant disease-free and overall survival (DDFS, OS) in an early BC cohort. Methods: 501 non-diabetic women with T1-3, N0-1, M0 BC diagnosed 1989-96 provided fasting blood (mean 7.7 ± 4.3 weeks after surgery, prior to systemic therapy, stored at -80°C) which was analyzed for hsCRP (Roche Elecsys immunochemistry). 359 women also completed the EORTC QLQ-C30 (mean 8 ± 3.9 weeks post-surgery). Women were followed prospectively to 2007. Data were analyzed using Spearman's rank correlation coefficients (r) and Cox models. Results: Mean age was 50.5 ± 9.7 years; 282/159/24/36 subjects had T1/T2/T3/TX cancers; 350 were N0; 306 had ER+ and 278 PgR+ cancers (HER2 was not performed); 76/208/142 cancers were grade 1/2/3; adjuvant treatment involved radiation (369 subjects), chemotherapy (196), tamoxifen (107). Median hsCRP was 0.9 mg/L (25th/75th percentiles: 0.4/2.4 mg/L). hsCRP was correlated (all p < 0.0001) with age (r = 0.25), Body Mass Index (BMI, r = 0.6), insulin (r = 0.44), Homeostasis Model Assessment (r = 0.45) and leptin (r = 0.54), but not with EORTC fatigue (r = 0.02), T or N stage, grade or ER/PgR status (any + vs. both -). Median follow-up was 12 years. hsCRP was not associated with DDFS or OS in univariate analyses (Q4 vs. Q1 HR 1.03, 95% CI 0.69-1.52, p = 0.9 and HR 1.27, 95% CI 0.86-1.86, p = 0.24 respectively) or multivariate analyses adjusting for age, T, N, grade, ER/PgR status, treatment (HR 1.02, 95% CI 0.66-1.59, p = 0.93 and HR 1.17, 95% CI 0.76-1.81, p = 0.48 respectively). Conclusions: hsCRP (measured post-op, prior to systemic therapy) was associated with age, BMI and obesity associated physiologic factors; it was not associated with fatigue, DDFS or OS. Funded by The Breast Cancer Research Foundation (New York), The Canadian Cancer Society Research Institute (formerly The Canadian Breast Cancer Research Initiative).

1120 Background: Sentinel lymph node biopsy (SLNB) is a widely used staging method for patients with early breast cancer. Neoadjuvant Therapy (NT) modifies the anatomical conditions in the breast and axilla, and thus reliability of SLNB after NT remains controversial. The aim of this study is to prospectively evaluate the feasibility and accuracy of this procedure in this particular group of patients. Methods: Between December 2007-2011, 69 patients (mean age 56 years) with locally advanced breast cancer (LABC) were prospectively studied. Patients were T1-4, N0-1, M0. Prior to surgery, 61 patients received chemotherapy (CT) (adryamicin/cyclophosphamide followed by docetaxel) and 8 patients endocrine therapy (ET). Thirty nine patients were initially node-negative (cN0) and 30 patients had clinical/ultrasound node-positive confirmed by cytology (cN1) at presentation. All patients were clinical and ultrasound node-negative after NT. The study contained two groups of patients: group A (validation) included the first 29, associated with an axillary lymph node dissection (ALND) after NT, in order to validate the study, and group B included the last 40, only associated with an ALND when SLNB was positive or not found. Results: Whole SLNB identification rate was 89.9%, and no significant differences were found between patients initially cN0 (92%; 36/39) and initially cN1 (87%; 26/30). Four of 7 patients in whom SLNB was not found had residual nodal metastasis after NT (3 of them were initially cN1). Sentinel lymph nodes were successfully identified in 87% (7/8) of patients after ET and in 90% (55/61) of patients after CT. There was one false negative (FN) case after CT in group A (9% of overall false negative rate, initially cN0) and there were no FN cases after ET. Positive SLNB were higher in initially cN1 group (53%; 16/30) than in initially cN0 group (18%; 7/39). Conclusions: SLNB after NT (CT or ET) is safe and feasible in patients with LABC, not only in initially cN0 but also in initially cN1. It accurately predicts the status of the axilla and avoids unnecessary ALND.

e14552 Background: MEK/ERK pathway is considered one of the main controllers of cell proliferation and survival and its deregulation has been involved in several tumors. Different mechanisms have been described leading to ERK activation and nuclear translocation including mutations on genes encoding pathway constituents', or upstream factors overexpression. Little is known about the status of this pathway in GC. The aim of our study was to evaluate the expression of different factors of this pathway in GC and their correlation with patient outcome. Methods: Fifty-eight patients with localized stage Ib-III GC who underwent radical surgery followed by adjuvant chemoradiotherapy were selected. ERK and its activated form (pERK) expression were analyzed by IHC, and KRAS and BRAF mutations were determined by PCR. Additionally, expression of upstream factors such as EGFR, HER2, VEGFR and downstream factor such as MST2 was evaluated by IHC. Finally, EGFR and HER2 copy number alterations were analyzed by FISH. Association of these markers to overall survival was assessed using the log rank test, and survival curves were plotted with Kaplan-Meier methodology. Results: Among the 58 tumors analyzed, 7% arose from the cardias and 33% corresponded to signet ring cell carcinomas. ERK and pERK expression was observed in the majority of tumors (86 and 64%, respectively, p=0.002). Cytoplasmic pERK expression did not show any association with the clinico-pathological characteristics. Notably, nuclear pERK (pERKnc) expression was observed in 12% of the cases and it showed a significant correlation with patient survival (p=0.05), conferring a worse prognosis. Moreover, EGFR overexpression (p=0.03) correlated with pERKnc. Finally, multivariate Cox analysis for survival confirmed that stage (HR 0.31, p=0.01) and pERKnc (HR 2.7, p=0.04) are unique independent prognostic factors. Conclusions: MEK/ERK pathway is commonly activated in localized GC, backed up by ERK and pERK being highly expressed in these tumors. Moreover, EGFR expression correlates with nuclear ERK expression, suggesting that ERK translocation to the nucleus could be mediated by this factor. More importantly, nuclear ERK has appeared as an independent marker of poor prognosis.

Background: The addition of trastuzumab (T) to neoadjuvant chemotherapy increases pCR rate in patients with HER2 + breast cancer. Lapatinib (L) in combination with chemotherapy is also an active drug in breast cancer patients. This study investigates the efficacy of trastuzumab or lapatinib added to chemotherapy in the neoadjuvant setting. Methods: Patients (Pt) with tumors greater than 2 cm (or less with positive axilla) and HER2+ (Herceptest 3+ or 2+ with FISH+) that have not received any prior treatment for breast cancer were recruited. Pts were randomized to receive epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 × 4 cycles (cy) followed by docetaxel 100 mg/m2 (with growth colony stimulating factor support) plus either T 8 mg/kg loading dose and then 6 mg/Kg intravenous (EC-DT) or L 1250 mg orally (EC-DL). Patients were stratified according to tumor size (T1-2 vs T3-4), and estrogen receptor status (positive vs negative). The primary end-point was pathological complete response (pCR) in the breast measured by Miller and Payne criteria. Secondary end-points were clinical response (by imaging test), toxicity and correlation between pCR and tumor biomarkers. Results: From February-09 to October-10, 102 pts were randomized (50 EC-DT, 52 EC-DL). Pts characteristics were well balanced between arms. Median age was 48 years (30-79), 56% of pts were premenopausal, 7% grade I, 45% grade III. 14/59/12/15% were T1/T2/T3/T4 and 69% N+. 58% were estrogen receptor positive and 44% progesterone receptor positive. Three patients were FISH negative after central assessment and were not considered evaluable for efficacy. pCR rate in the breast was 52% (95% CI: 38–66) for EC-DT and 25% (95% CI: 13.5−37.5) for EC-DL (p-value=0.0065). pCR—pN0 was 48% (95% CI: 34–62) for EC-DT and 24% (95% CI: 12 - 35) for EC-DL (p-value=0.01). Clinical response was 77% with EC-DT and 65% with EC-DL (p-value=0.176). Grade III-IV toxicity was similar between arms except for diarrhea that was more frequent in EC-DL 14% than in EC-DT 2% (p-value=0.03); more patients discontinue treatment due to toxicity with EC-DL (1 vs 6; p-value=0.055). Conclusions: Our study shows that EC-DT was more efficacious and less toxic than EC-DL in the neoadjuvant treatment of HER2+ pts. Biomarker profiling in the tumors, including activation levels of tyrosine-kinase receptors, signaling pathways and surrogate markers (proliferation and apoptosis) is ongoing; their correlation with pCR will be presented at the meeting. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD07-04.

21505 Background: Prognostic factors for GS used in available studies are the presence of metastasis, performance status and factors included in FIGO staging. The objective of this retrospective study was to analyze clinical and pathological prognostic factors, trying to improve the usual (FIGO) classification. Methods: We analyzed 75 patients with ovarian (11) or uterine sarcoma (64) diagnosed from 6/1983 to 12/2007. Pathology: 26 leiomyosarcoma, 35 carcinosarcoma, 10 endometrial stromal, 4 high-grade undifferentiated sarcoma. Results: Medium age was 57 (26–82) years. With a median follow-up of 30.4 months (6–305), 5-year and 10-year survival was 71% and 69%. Survival significant prognostic factors in the univariate analysis: histologic subtype (stromal 100%, leiomyo 69%, carcinosarcoma 64%, undifferentiated 50%, p=0.01); tumor grade (I=100%, II=80%, III=58%, p=0.0003); AJCC sarcoma staging (I=100%, II=71%, III=68%, IV=55%, p=0.005); FIGO staging (I=89%, II=67%, III=58%, IV=50%, p=0.004). Disease relapse...