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Background It has been suggested that the results from fragile trials are less likely to translate into benefit in routine clinical practice. Methods We searched the Food and Drug Administration (FDA) archives to identify drug approvals for solid organ malignancies between 2010 and 2019. We calculated the Fragility Index (FI) supporting each approval, using methods to account for time‐to‐event. We compared FI and trial and approval characteristics using Mann‐Whitney U and Kruskal‐Wallis test. Using logistic regression, we examined study characteristics associated with withdrawal of consent or lost to follow‐up (WCLFU) exceeding the calculated FI. Results The median FI among 125 included studies was 23 (range 1–322). The FI was ≤10 in 35 studies (28%), 11–20 in 21 (17%), and >20 in 69 (55%). The median FI/Nexp was 7.7% (range 0.1–51.7%). The median FI was significantly lower among approvals processed through the accelerated vs regular pathway (5.5 vs 25, p = 0.001), but there was no difference in median FI/Nexp. The WCLFU exceeded FI in 42% of studies. Overall survival endpoints were more likely to have a WCLFU exceeding FI (OR 3.16, p = 0.003). WCLFU exceeding FI was also associated with a lesser magnitude of effect (median HR 0.69 vs 0.55, p FI. Conclusion The median FI among all trials was 23, and WCLFU exceeded FI in 42%. Comparative trials in solid tumors supporting approval through the accelerated pathway are more fragile compared to trials approved through the regular pathway, an observation likely explained by a lower sample size in the experimental arm., Trials in solid tumors supporting accelerated approval are more fragile compared to regular approvals. This finding supports the need for post‐marketing trials or real‐world analyses to ensure the benefit observed in clinical trials is robust and reproducible.

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.

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: Most anticancer drugs are approved by regulatory agencies based on surrogate measures. This article explores the variables associated with overall survival (OS), quality of life (QoL), and substantial clinical benefit among anticancer drugs at the time of approval and in the postmarketing period. Methods: Anticancer drugs approved by the FDA between January 2006 and December 2015 and with postmarketing follow-up until April 2019 were identified. We evaluated trial-level data supporting approval and any updated OS and/or QoL data. We applied the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) and the ASCO Value Framework (ASCO-VF) to initial and follow-up studies. Results: We found that 58 drugs were approved for 96 indications based on 96 trials. At registration, approval was based on improved OS in 39 trials (41%) and improved QoL in 16 of 45 indications (36%). Postmarketing data showed an improvement in OS for 28 of 59 trials (47%) and in QoL for 22 of 48 indications (46%). At the time of approval, 25 of 94 (27%) and 26 of 80 scorable trials (33%) met substantial benefit thresholds using the ESMO-MCBS and ASCO-VF, respectively. In the postmarketing period, 37 of 69 (54%) and 35 of 65 (54%) trials met the substantial benefit thresholds. Drugs with companion diagnostics and immune checkpoint inhibitors were associated significantly with substantial clinical benefit. Conclusions: Compared with the time of approval, more anticancer drugs showed improved OS and QoL and met the ESMO-MCBS or ASCO-VF thresholds for substantial benefit over the course of postmarketing time. However, only approximately half of the trials met the threshold for substantial benefit. Companion diagnostic drugs and immunotherapy seemed to be associated with greater clinical benefit.

Objective To investigate whether US Food and Drug Administration approval of new drugs without randomization or an active drug comparator is associated with more postmarketing safety-related label modifications. Methods We searched Drugs@FDA for new drugs approved from January 1, 1999, through December 31, 2014. Drugs approved without supporting randomized controlled trials (RCTs) were matched to between 1 and 2 controls from similar therapeutic categories approved with supporting RCTs within 3 years of the reference drug. Study characteristics, regulatory pathways, and label modifications up to December 2017 were collected from drug labels. Differences in postmarketing safety modifications between cases and controls were assessed using conditional logistic regression. Results The study cohort included 52 drugs approved without supporting RCTs and 91 matched controls. Drug approvals not supported by RCTs were associated with lower sample size (odds ratio [OR] per 100 patients, 0.77; 95% CI, 0.68-0.87) and were more likely to receive orphan drug designation (OR, 5.10; 95% CI, 2.23-11.69), fast-track designation (OR, 4.80; 95% CI, 2.25-10.23), and accelerated approval (OR, 7.00; 95% CI, 3.14-15.60). Drugs approved without supporting RCTs were associated with more modifications in black box warnings (28.8% vs 13.2%; OR, 2.67; 95% CI, 1.13-6.27), warnings and precautions (73.1% vs 52.7%; OR, 2.43; 95% CI, 1.16-5.09), and common adverse reactions (48.1% vs 23.1%; OR, 3.09; 95% CI, 1.49-6.41). Conclusion Food and Drug Administration approval of new drugs without supporting RCTs is associated with more postmarketing safety-related label modifications than drugs approved with supporting RCTs. Robust postmarketing studies are required for drugs approved without supporting RCTs. Health care professionals should be vigilant for unrecognized adverse effects when prescribing these drugs.

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 Modifications of primary outcome measures after trial initiation can undermine their scientific validity. We aimed to quantify these changes and to characterize potential predictors in clinical drug trials published in high impact factor general medicine journals. Methods The study cohort included all prospective, adult drug clinical trials published in the New England Journal of Medicine, JAMA and Lancet between June 2017 and May 2018. The matching ClinicalTrials.gov entries effective at trial initiation were compared with those effective on July 2018, thereby identifying amendments to primary outcome definitions and assessment timeframes and the planned sample size (defined as >10% change). The primary publications were reviewed for reporting of these amendments. Associations between identified changes and trial characteristics were explored using logistic regression. Results Of the 147 included trials, modifications to primary outcome measures were identified in 80 (54%). Primary outcome definitions, outcome assessment timeframes and the planned sample size were modified in 28 (19%), 12 (8%) and 65 (45%) of registry entries, respectively; of which 21 (75%), 11 (92%), and 33 (51%), respectively, were not reported in the related publications. There were no significant associations between modifications in registry entries and study characteristics. Conclusions Approximately half of trials published in influential medical journals present changes to the design while patient accrual is ongoing, and two thirds of them are unreported. Justification for such modifications should be reported more clearly. Reviewers, editors and readers should consult ClinicalTrials.gov for a more comprehensive report of the evolution of key study methods.

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.

Background: It is uncertain whether drugs approved by the US Food and Drug Administration (FDA) have clinically meaningful benefit as determined by validated scales such as the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Methods: We searched the Drugs@FDA website for applications of anticancer drugs from January 2006 to December 2016. Study characteristics, outcomes, and regulatory pathways were collected from drug labels and reports of registration trials. For randomized controlled trials (RCTs), ESMO-MCBS grades were applied. Meaningful benefit was defined as a grade of A or B for (neo)adjuvant intent and 4 or 5 for palliative intent. All statistical tests were two-sided. Results: We identified 63 individual drugs for 118 indications. These were supported by 135 studies, among which were 105 RCTs for which ESMO-MCBS could be applied. Only 46 (43.8%) met the ESMO-MCBS meaningful benefit threshold (100% of (neo)adjuvant trials and 38.8% of palliative trials). In palliative therapy trials, meaningful ESMO-MCBS grades were associated with phase III trials (compared with phase II; odds ratio [OR] = 38.45, 95% confidence interval [CI] = 3.27 to 452.00, P = .004), those with overall survival as their primary end point (compared with intermediate end points; OR = 8.28, 95% CI = 2.49 to 27.50, P = .001) and trials of targeted drugs with companion diagnostics (OR = 11.62, 95% CI = 2.95 to 45.78, P < .001). Over time, there has been an increase in the number of trials meeting the ESMO-MCBS threshold (P-trend = .04). There were insufficient (neo)adjuvant studies to perform statistical analysis. Conclusions: The number of trials meeting the ESMO-MCBS threshold for clinical benefit has improved over time. However, fewer than half of RCTs supporting FDA approval meet the threshold for clinically meaningful benefit.

This study describes sources of initial safety signals that that preceded US Food and Drug Administration (FDA) drug safety communications and examines their associations with drug characteristics and subsequent label changes.

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.

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.

Purpose Modifications in cancer drug indications, dosing, and related toxicities after Food and Drug Administration approval are common. It is unclear whether drug approval without a supporting randomized controlled trial (RCT) influences the probability of such modifications. Methods We searched the Drugs@FDA Web site for new drug indications for solid tumors approved between January 2006 and December 2016. Study characteristics, regulatory pathways, and label modifications from approval to October 2017 were collected from drug labels. Label modifications were considered to be major if defined as such in the drug label. Indications approved with and without supporting RCTs were compared using logistic regression. The Benjamini-Hochberg false discovery rate method was used to adjust for multiplicity. Results We identified 59 individual drugs for 109 solid tumor indications. Of these, 17 indications (15.6%) were not supported by an RCT, with no change over time. Indications not supported by RCTs were more likely to require companion diagnostic tests (odds ratio [OR], 3.90; P = .02), to include surrogate end points as primary outcomes (OR, 7.88; P < .001), and to receive breakthrough therapy designation (OR, 7.62; P = .006) or accelerated approval (OR, 17.67; P < .001). Indications not supported by RCTs were associated with significantly higher odds of postapproval modifications in common adverse events (71% v 29%; OR, 5.78; P = .002). A nonsignificantly higher odds of postapproval major modifications in warnings and precautions was also observed (88% v 62%; OR, 4.61; P = .051). Postapproval major modifications in indication and usage, dosing and administration, boxed warnings, and contraindications were comparable in the two groups. Conclusion Cancer drug indications not supported initially by RCTs are associated with more postmarketing safety-related label modifications. Health care professionals should be vigilant for unrecognized adverse effects when prescribing drugs approved without a supporting RCT.

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 Clinical trials supporting approval for new drugs often evaluate surrogate endpoints, and data on meaningful outcomes like OS or QoL may not be available. Here, we evaluated changes in the magnitude of clinical benefit, OS and QoL after approval. Methods We examined data on pivotal trials supporting FDA accelerated (AA) and regular (RA) cancer drug approvals between January 2006, and December 2015. For AA drugs, if conversion to RA was granted, only the confirmatory trial was analysed. To determine any new evidence on OS and QoL in the postmarketing period (PMP) we performed a systematic search of Pubmed and ClinicalTrials.gov. European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) grades were applied for trials at approval and in the PMP. Substantial clinical benefit was defined as a grade of A or B for trials of curative intent and 4 or 5 for those of palliative intent. Results We identified 96 pivotal trials supporting the approval of 47 drugs for 94 solid tumour indications. Of these indications, 22 (23%) were granted AA and 21 (22%) were converted to RA. At time of approval, 45 (48%) trials showed improved OS, 15 (16%) improved QoL and 33 (34%) had substantial clinical benefit. With a median PMP of 3.7 years, 50 (52%) trials reported OS data and 27 (28%) on QoL. Of these, 48 could be graded by the ESMO-MCBS. Of the updated 51 trials approved based on surrogate endpoints, only 7 (14%) showed an improvement in OS. In advanced disease, out of 74 trials for which there was no evidence on QoL at the time of approval, 12 (16%) showed improved QoL subsequently. Updated results led to changes in clinical benefit in 11 trials (10 upgrades, 1 downgrade) with 30 (62%) showing substantial clinical benefit. Among all trials, 52 (54%) showed improved OS, 27 (28%) improved QoL and 42 (44%) met the threshold for substantial clinical benefit. Conclusions After 3.7 years of post-marketing time, 54% of FDA approved cancer drugs showed statistically significant improvement in OS and 28% in QoL. Less than a half of trials supporting FDA approval met the threshold for substantial clinical benefit using ESMO-MCBS. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure E. Amir: Speaker Bureau / Expert testimony: Genentech/Roche; Advisory / Consultancy: Apobiologix; Advisory / Consultancy: Agendia; Advisory / Consultancy: Myriad Genetics. All other 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.

Low-density lipoprotein receptor-related protein 1, a member of the low-density lipoprotein cholesterol receptor family, has been implicated in the progression of certain tumors; but it remains unclear whether it plays a role in infiltrating ductal breast carcinomas. We studied a series of 81 ductal breast tumors to determine the correlation of low-density lipoprotein receptor-related protein I overexpression with clinicopathologic and immunohistochemical characteristics associated with prognosis. Low-density lipoprotein receptor-related protein I overexpression was identified in 14% (11/81) of tumors and was correlated with a high nuclear grade (P = .043), high mitotic index (P = .006), and Ki-67 greater than 20% (P = .047). Furthermore, low-density lipoprotein receptor-related protein 1 expression was associated with aggressive carcinomas (triple-negative tumors [21%, 7/33] and Her-2/neu tumors [17%, 4/24]) but not with hormone-dependent carcinomas (0%, 0/24)(P = .040). There was no correlation between low-density lipoprotein receptor-related protein 1 expression and survival, but a trend was found between low-density lipoprotein receptor-related protein 1 overexpression and tumor recurrence. Low-density lipoprotein receptor-related protein 1 overexpression was related to proliferation and invasiveness in Her-2/neu and triple-negative breast carcinoma. Moreover, patients with low-density lipoprotein receptor-related protein 1-positive tumors had higher cholesterol levels (62.5%, 5/8) than those with low-density lipoprotein receptor-related protein 1-negative tumors (40%, 19/47). Nevertheless, the correlation between low-density lipoprotein receptor-related protein 1 and hypercholesterolemia was not statistically significant; but cholesterol levels were higher in patients with triple-negative breast carcinoma (60%, 15/25) and Her-2/neu carcinomas (40%, 6/15) than in luminal-A carcinomas (20%, 3/15) (P = .046). These findings suggest a relationship between hypercholesterolemia and aggressiveness of ductal breast carcinomas. (C) 2011 Elsevier Inc. All rights reserved.

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).

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.

e20636 Background: Physicians and nurses had underestimated the incidence of chemotherapy-induced nausea and vomiting (CINV) after both high emetogenic chemotherapy (HEC) and moderately emetogenic chemotherapy (MEC) (Grumberg, Cancer 2004;100:2261–8; Erazo Valle, Curr Med Res Opin 2006;22:2403–10). We have assessed if physicians and nurses’ perception of CNIV in their own practices after the introduction of Aprepitant was closer to reality. Methods: A prospective, observational unicenter study of adult patients receiving their first chemotherapy cycle was performed. Medical oncologists and oncology nurses also estimated the incidence of acute (Day 1) and delayed (Days 2–5) CINV after first administration of HEC and MEC. Eligible patients completed a 6-day diary including emetic episodes, nausea assessment, and antiemetic medication use. Observed incidence rates of acute and delayed CINV were compared with physician/nurse predictions. Results: Twenty-nine physicians and nurses and 95 patients (86.3% receiving HEC and 13.7%MEC) were recruited. Acute nausea and emesis were observed in 14.3% and 2.4% respectively of HEC patients receiving Aprepitant, and delayed nausea and emesis were observed in 14.3% and 7.1% of these patients, respectively. Physicians and nurses accurately predicted the incidence of acute and delayed CINV after HEC patients receiving Aprepitant. Acute nausea and emesis were observed in 22.2% and 0% respectively of MEC patients and delayed nausea and emesis in 33.3% and 22.2% of MEC patients, respectively. All physicians and nurses underestimated the incidence of acute nausea and delayed nausea and emesis after MEC by 15, 28 and 18 percentage points, respectively. Conclusions: The addition of aprepitant in the prevention of CINV after HEC allows a better control of CINV that is perceived accurately by physicians and nurses. By contrary, physicians and nurses continue markedly underestimating the incidence of CINV after MEC. CINV still remain important targets for improved therapeutic intervention and physicians and nurses must be aware about the real incidence of CNIV. No significant financial relationships to disclose.

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...