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Background: Triple negative breast cancer (TNBC) is well known for its more aggressive course and poorer prognosis compared to other BC subtypes. RegistEM study provides real world data to understand the distribution of BC subtypes in the advanced setting, being its primary objective. Biological samples collection is part of its procedures. This is a non-interventional cohort study and 1,907 patients (pts) have been enrolled up to now (females and males) with advanced BC (ABC), diagnosed from Jan-2016 to Dec-2019, either after recurrence or as first BC diagnosis, in 38 Spanish sites. These pts will be followed for at least 5 years. Methods: In the current analysis (cut-off date 08/April/2022, database ongoing), we describe characteristics, treatment patterns and outcomes, including comparison between recurrent and de novo disease, of 157 pts with advanced TNBC included in the RegistEM study. Those pts represent the 10% of pts available in the database at the cut-off date and with ABC diagnosis up to December 2018 (n=1559). The BC clinical subtypes were histologically confirmed on the most recent tumor lesion (metastatic [M] or primary BC) before starting with the 1st-line therapy. Results: At first ABC diagnosis, 73% pts had recurrent early BC (EBC), 26% de novo MBC and 1% unresectable locally ABC (ULABC). Median age was 57 years (range 30-88), all pts were women, 98% Caucasian and 65% postmenopausal. Family history of BC and/or ovarian cancer was reported in 37% pts, and a hereditary-risk genetic test was performed in 59 of 147 pts. Germline BRCA1/2 and TP53 were the most frequently mutated genes, 21% (6/28) and 47% (8/17) pts, respectively. Visceral involvement was present in 69% pts (similar between recurrent EBC and de novo ABC, although brain metastases were only present in the recurrent EBC group), and ≤ 2 metastatic locations in 59%. In 61% (70/115) pts with recurrent EBC, the subtype was assessed in metastatic lesions, and 39 pts of them also had TN subtype in primary BC. In terms of the most frequent therapies by line: 1) 1st-line: chemotherapy (CT) (60%) and CT/biological therapy (BT) (39%). Of the 87 pts with CT alone, monotherapy was the preferred option in 57% pts (capecitabine 25%, taxanes 16%, and eribulin or vinorelbine, 5% each). Bevacizumab was the most frequent BT (79%) combined with CT (single agent in 56% pts, mostly taxanes and capecitabine). Progressive disease (PD) was reported in 85% pts (similar in pts with both recurrent and de novo MBC or ULABC); 2) 2nd-line: CT (79%) (monotherapy capecitabine, eribulin, taxanes) and CT/BT (17%) (CT-containing bevacizumab 82%). Progression was reported in 92% pts; 3) 3rd-line: CT (90%) (eribulin 33%, platinum-based 25%) and CT/BT (9%) (CT-containing bevacizumab 67%). Progression was reported in 88% pts. At database cut-off date, death was reported in 133 (85%) pts, mainly because of PD. Overall survival (OS) was similar between both groups, recurrent and de novo MBC. Conclusion: In this population of Spanish TNBC pts with ABC, three quarters had recurrent disease. De novo ABC pts had a higher proportion of non-visceral metastases, with absence of brain involvement at the first diagnosis. Single-agent CT and CT plus bevacizumab were the most frequent therapies, and OS was similar between recurrent and de novo MBC pts, although numerically higher in the later group. Citation Format: Silvia Antolin Novoa, César A Rodríguez, Josefina Cruz, Sara López-Tarruella, Ariadna Tibau, Encarna Adrover, Ana Miguel, Mireia Margelí, Purificación Martínez, María Hernández, Antonio Antón, Álvaro Rodríguez-Lescure, Catalina Falo, Isabel Álvarez, Diego Malón, Raquel Andrés, José L Alonso-Romero, César Gómez, J. José Illaramendi, Ruth Campo, Juan José Miralles, Susana Bezares, Federico Rojo, Angel Guerrero-Zotano. Treatment strategies for advanced triple negative breast cancer patients as per routine clinical practice: analysis from the observational study GEICAM/2014-03 (RegistEM) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-45.

Background: HER2-low breast cancer (BC) is a new therapeutic entity, but it is uncertain if this subgroup of BC differs from HER2-negative tumors in clinical characteristics, prognosis, and response to therapy. The objective is to describe the clinical characteristics and outcomes of 422 patients (pts) with HER2-low BC documented before 1st line, having been diagnosed with advanced BC (ABC) before 2019 and included in the RegistEM study (n=1,663). Methods: In this analysis (cut-off date 08/April/2022; database is ongoing), two subgroups of pts have been considered based on HER2 results: HER2-low (n=422) (immunohistochemistry [IHC] 1+ or IHC 2+ and in situ hybridization [ISH] negative) and HER2-IHC 0 (n=590), as reference. Hormone Receptor (HR) expression has also been considered for subgroup analysis. Results: At first ABC diagnosis, < 1% pts had unresectable locally advanced BC (ULABC) in both groups, 31% de novo metastatic BC in HER2-low and 20% in HER2-IHC0 groups. Less than 1% were male, 99% Caucasian and ~71% postmenopausal. Median age was 60 years, being similar between both groups (range 26-96). Family history of BC and/or ovarian cancer was reported in 32% pts in HER2-low and 29% in HER2-IHC0. Germline BRCA1/2 mutation was higher in HER2-low (14/40=35%) in reference to HER2-IHC0 (14/64=22%) (p=0.14). Relevant information summarized by HR expression and HER2 status are detailed in the table below. Visceral disease was similar in both total groups (58% in HER2-low vs HER2-IHC0 56%), but slightly higher in HR- HER2-low pts (81% vs 64%), and 84% and 90% pts had ≤3 metastatic locations, in HER2-low and HER2-IHC0 groups, respectively. Distribution of 1st-line therapies was also similar between both groups, being endocrine therapy (ET) plus biological therapy (BT) (HER2-low 39% vs HER2-IHC0 36%) and ET (HER2-low 30% vs HER2-IHC0 28%), while chemotherapy (CT) (HER2-low 13% vs HER2-IHC0 16%) and CT plus BT (HER2-low 9% vs HER2-IHC0 10%) were more frequent in HR- pts. A 2nd-line therapy was reported in 70% HER2-low pts and 67% HER2-IHC0 pts. The median time to progression (TTP) at 1st-line therapy in HER2-low pts was 11 mo (0-66), being similar in HER2-IHC0 pts, but the higher difference was observed in relation to HR expression. Treatments in 2nd-line were similar in both groups, CT and ET/BT were the most frequent totally. Median duration of 2nd-line therapy was ~6 mo; progressive disease (PD) was reported in 85% pts. A 3rd-line therapy was reported in 74% HER2-low and 69% HER2-IHC0 pts. The median time to progression (TTP) to 3rd-line therapy was 6 mo, being similar in HER2-low and HER2-IHC0 pts .The most frequent 3rd-line therapies were CT and ET/BT in both groups, as in 2nd-line. Median duration of 3rd-line therapy was 4 mo; PD was reported in 84% HER2-low pts and 82% HER2-IHC0 pts. Median (95% confidence interval [CI]) PFS at 1st, 2nd and 3rd lines (mo) were 14 (12-16), 6 (5-7) and 6 (5-6) in HER2-low pts, being similar in HER2-IHC0. OS was comparable in all soubgroups analyzed, however, differences were observed regarding HR status. Conclusions: Our results show that HER2-low BC pts have similar characteristics than HER2-IHC0 BC pts. There are differences in therapy outcomes in terms of survival and prognosis, particularly in HR- tumors, being better in HER2-low BC pts. It could be related to the fact that these tumors have a specific biology, but more evidence is needed. Citation Format: Isabel Álvarez, Angel Guerrero-Zotano, Ariadna Tibau, Catalina Falo, María Hernández, Ana Miguel, Raquel Andrés, Álvaro Rodríguez-Lescure, Miguel Corbellas, Sara López-Tarruella, Purificación Martínez, Cesar A Rodríguez, Diego Malón, María Marin, Mª José Echarri, Antonio Antón, Josefina Cruz, Diana Moreno, J. Ignacio Chacón, Ruth Campo, Andrea Blasco, Susana Bezares, Federico Rojo, Silvia Antolin. Features and survival outcomes of HER2-low patients from a prospective registry of unresectable locally advanced or metastatic breast cancer: GEICAM/2014-03 (RegistEM) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-30.

Background: Over the last years, the treatment of HER2-positive (HER2+) breast cancer (BC) patients (pts) has been changing because of the development of new anti-HER2 agents. In the current analysis, we describe the features, treatment patterns, progression-free survivall (PFS) and overall survival (OS) outcomes of BC pts with HER2 + (immunohistochemistry [IHC] 3+ or IHC 2+ and in situ hybridization [ISH]+), following ASCO/CAP 2018 guidelines in the most recent tumor lesion before the 2nd-line. Methods: The RegistEM study is an ongoing BC registry study that is providing prospective data from around 1900 pts diagnosed with advanced BC (ABC) between 01/Jan/2016 and 31/Dec/2019, in 38 Spanish institutions from GEICAM network. In this analysis, 296 HER2+ BC pts have been included, representing the 18% of pts available in the database at the cut-off date (08/Apr/2022), with ABC diagnosis before 2019 (n=1559). Results: At first ABC diagnosis, 58% (n=173) pts had recurrent disease (>36 months [mo] from initial BC diagnosis in 62%), 41% (n=120) de novo metastatic BC and 1% (n=3) unresectable locally ABC (ULABC); the median age was 58 years, 68% were postmenopausal and there was only 1 male pt. From total 296 pts, 66% had hormone receptor expression [HR+]; the BC subtype was assessed in tumor tissue from the breast (58%) or a metastatic lesion (34%), and in 8% pts, HER2 positivity was observed after the 1st-line. Family history of BC and/or ovarian cancer was reported in 28% pts, and a hereditary-risk genetic test was performed in 26% pts (n=74/282). Germline BRCA1/2 and TP53 genetic testing were reported in 14 and 26 pts respectively, being mutated in 3/14 (21%) and 5/26 (19%) pts. Bone (50%), lymph nodes (49%), liver (35%), lung (31%), soft tissue (8%) and central nervous system (CNS), mostly in brain (8%), were the main metastatic sites. One hundred pts were diagnosed with CNS metastases: 24 at baseline, 48 during the 1st-line and 28 in subsequent lines. Additional data according to HR status and type of ABC are detailed in the table below, showing a worse prognosis in absence of HR expression. In HR- pts, bone metastases were less frequent and lymph nodes metastases more frequent compared to HR+ pts. Visceral disease was present in 69% (66% in HR+ and 74% in HR-; non-statistically significant) pts and ≈80% had ≤3 (54%, ≤2) locations involved. The most common therapies by line were: 1) 1st-line: Chemotherapy (CT) + biological therapy (BT) (38%), CT + BT+ endocrine therapy (ET) (35%), and ET + BT [11%]; 2) 2nd-line: BT (55%), CT + BT (20%) and ET + BT (15%); 3) 3rd-line: CT + BT (49%) and BT (31%). The median (95% confidence interval [CI]) progression-free survival (PFS) on 1st, 2nd and 3rd line was 18 (15-22), 8 (7-9) and 6 (5-8) mo, respectively. The median (95% CI) overall survival (OS) from ABC diagnosis was 43 (40-49) mo. These survival outcomes were higher in HR+ pts, however, the differences were only statistically significant in OS (p=0.006; log-rank). At database cut-off date, death was reported in 47% pts. Conclusions: In spite of the anti-HER2 therapies administered in the advanced setting, the HR expression is a relevant prognostic factor, with a clinically and statistically significant impact in OS, improving the outcomes of HR+ pts. Citation Format: Sara López-Tarruella, Angel Guerrero-Zotano, Josefina Cruz, Silvia Antolin Novoa, Purificación Martínez, María Hernández, César A Rodríguez, J. Ignacio Chacón, Ariadna Tibau, Catalina Falo, Álvaro Rodríguez-Lescure, Mireia Margelí, Sonia Servitja, Raquel Andrés, María Galán-Gramaje, Encarna Adrover, Ana Miguel, Rafael Villanueva, Silvia Varela, Ruth Campo, Mª José Escudero, Susana Bezares, Federico Rojo, Isabel Álvarez. Real-world data of Advanced Breast Cancer (ABC) patients with HER2-positivity before the second-line therapy: data from the observational study GEICAM/2014-03 (RegistEM) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-38.

Background: The RegistEM study is a non-interventional study that is providing prospective data from around 1900 ABC pts (females and males) diagnosed with advanced disease between 01/Jan/2016 and 31/Dec/2019, either after recurrence or at 1st diagnosis, in 38 Spanish sites representative of the national territory and whose investigators are GEICAM members. Methods: In the current analysis (cut-off date 10/May/2021, ongoing database), we describe the features of 279 pts included in the RegistEM study, with HER2+ (immunohistochemistry [IHQ] 3+, IHQ 2+ and in situ hybridization [ISH]+) tumors at any time of their ABC (5% after the 1st-line therapy). This subgroup has been evaluated because of the interest from a clinical perspective. Multivariate Cox analysis aiming to identify factors associated with overall survival (OS) were built. Results: 279 pts were identified, representing the 15% pts available in the database at the cut-off date. At first ABC diagnosis, 48% pts had recurrent BC (>12 months [mo] from initial BC diagnosis in 93%), 51% de novo metastatic BC and 1% unresectable locally advanced BC (ULABC). The median age was 59 years, 98% were white , 71% postmenopausal and only 1 male was part of this subset. Considering the BC subtype assessed in the most recent tumor lesion before the 1st-line therapy, 264 pts wereHER2 positive (67% with hormone receptor [HR]+). Family history of BC and/or ovarian cancer was reported in 31% pts, and an hereditary-risk genetic test was performed in 25% (66/267 pts). BRCA1/2 and TP53 mutations were reported in 4/20 and 4/19 pts, respectively, and p53 overexpression in 20/46 pts. Lymph nodes (56%), bone (49%), liver (34%), lung (33%), soft tissue (10%) and brain (8%) were the main metastatic sites. Additional data according to HR status and type of ABC are detailed in the table below. In HR- pts, bone metastases were less frequent and lymph nodes metastases more frequent compared to HR+ pts. Visceral disease was present in 68% pts and ≈75% had ≤3 (47% ≤2) locations involved. The most common therapies by line were: 1) 1st-line: CT + dual anti-HER2 blockade (3%), chemotherapy (CT) (almost in all pts taxane-based)+dual anti-HER2 blockade + endocrine therapy (ET) (mainly aromatase inhibitors) (35%), and ET + anti-HER2 blockade or ET + cyclin-dependent kinases 4/6 inhibitors (11%); 2) 2nd-line: anti-HER2 blockade (56%) [mostly an antibody-drug conjugate (90%)], CT + anti-HER2 blockade (18%) and ET + anti-HER2 blockade (14%); 3) 3rd-line: CT + anti-HER2 blockade (55%) and anti-HER2 blockade (22%). The median time-to-progressions to 1st-, 2nd- and 3rd-line were 14, 5, and 4 mo, respectively. A 4th-line therapy was reported in 52% of pts who received a 3rd-line. At database cut-off date, death was reported in 34% of pts. The median OS of this subset of pts was 41 mo (36-49). In a multivariate Cox regression analysis, the following variables were significantly related with worse survival (from ABC diagnosis): Brain (HR=2.62; 95% CI, 1.02-6.73) and Visceral no Brain involvement (HR=2.15; 95% CI, 1.02-4.53) compare to only soft tissue lesions; early stage at first diagnosis (HR=1.77; 95% CI, 1.15-2.73); HR- (HR=1.70; 95% CI, 1.11-2.60) and age (HR=1.04; 95% CI, 1.02-1.07). Conclusions: In this cohort of HER2+ pts with advanced disease, half of them had de novo ABC which was associated with better OS. The median PFS in 1st- and 3rd-line were slightly better in HR+ pts, and in 2nd-line was similar between HR+ and HR- cohorts. HR+181 (67%)HR- 91 (33%)Recurrent EBC134 (48%)ULABC or de novo M1 145 (52%)Time to recurrence >12 mo in EBC pts., n8435125NALocation of metastaticsites, nBoneBrainLiverLungLymph nodesSoft tissue104 10 62 57 90 1829 9 3232 64 1059 15 36 47 51 2278 6 59 46 1056Líne123123123123n180935690492613385521446333Deaths, n211112111161715141584Therapies by line, nET/BT261922101910212100ET12441011022323CT/BT/ET935031038305830CT/BT4017307581552182366924CT3572353711211BT6431373651145143385The most frequent therapies, nCT + dual anti-HER2 blockade + ET8623331551CT + single-agent HER2 blockade + ET522CT + dual anti-HER2 blockade3493644391016252CT + single-agent HER2 blockade4825641588211521CT5573354711411ET*22105212162644ET + HER2 blockade1213411662782Anti-HER2 blockade6431073651145143382Median duration of treatment, mo125585310441064TTP (mo), median (range)15(1-47)5(1-32)5(0-18)11(2-38)5(1-27)4(2-12)12 (1-47)5(1-26)4(0-17)17(2-45)7(1-32)4(1-18)Median PFS, mo14561154------HR: hormone receptor; EBC: early breast cancer; ULABC: unresectable locally advanced breast cancer; M1: metastatic; mo: month; ET: endrocrine therapy; BT: biological therapy; CT: chemotherapy; TTP: time-to-progression; PFS: progression-free survival. *ET includes aromatase inhibitors or selective estrogen receptor degraders, as single-agents or combined with cyclin-dependent kinases 4/6 inhibitors. Citation Format: Isabel Álvarez, Ángel Guerrero-Zotano, Josefina Cruz, Purificación Martínez, María Hernández, César A Rodríguez, Álvaro Rodríguez-Lescure, Silvia Antolín, Encarna Adrover, Raquel Andrés, Catalina Falo, Jose Ignacio Chacón, Ana Miguel, Sonia Servitja, Maria Galán Gramaje, Mireia Margelí Vila, César Gómez Raposo, María Jose Echarri, Rafael Villanueva, Ariadna TIbau Martorell, Silvia Varela Ferreiro, Ruth Campo, Juan Jose Miralles, Susana Bezares, Federico Rojo, Sara López-Tarruella. Features of HER2+ metastasic patients (pts) from a prospective registry of advanced breast cancer (ABC), GEICAM/2014-03 (RegistEM) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-15-04.

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.

e18604 Background: Oncology societies have developed tools to quantify the magnitude of clinical benefit. These include the American Society of Clinical Oncology Value Framework (ASCO-VF) version 2, the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) version 1.1, the National Comprehensive Cancer Network (NCCN) Evidence Blocks and the ASCO Cancer Research Committee criteria (ASCO-CRC). Associations between the characteristics of approved drugs and magnitude of clinical benefit have been explored in depth. Here, we assess the association between characteristics of control group therapy and magnitude of clinical benefit. Methods: We searched Drugs@FDA to identify new solid tumor cancer drugs approved based on randomized trials (RCTs) between January 2012 and December 2021. Substantial clinical benefit was defined as: overall survival gain ≥ 2.5 months and progression-free survival gain ≥ 3 months for the ASCO-CRC (palliative setting only); ASCO-VF threshold score ≥45 (palliative and curative setting); NCCN Evidence Blocks threshold score ≥16 (palliative and curative setting); and grade A or B for trials of curative intent and 4 or 5 for those of non-curative intent using ESMO-MCBS. Associations between characteristics of control group therapy (e.g. type of active therapy, use of matched placebo and overlap between experimental and control therapy) and substantial clinical benefit scores were explored using logistic regression. Results: We identified 174 RCTs supporting the approval of 76 drugs for 164 indications. Of these, 47% (82/174) were placebo-controlled trials among which 42% (34/82) comprised active treatment with a matched placebo. Substantial clinical benefit was observed in 45%, 46%, 72% and 73% using the ESMO-MCBS, ASCO-VF, NCCN Evidence Blocks and ASCO-CRC, respectively. These low proportions resulted in an inability to fit multivariable models adequately. RCTs with a control group comprising of active treatment with a matched placebo were associated with significantly lower odds of substantial benefit with ESMO-MCBS (OR 0.27, P = .003) and ASCO-VF (OR 0.30, P = .008) but not with NCCN Evidence Blocks (OR 0.74, P = .55) or ASCO-CRC criteria (OR 1.36, P = .54). Similar results were observed when excluding trials in the curative setting. There was a non-significant association with higher odds of substantial benefit with ESMO-MCBS with trials in which the control group was chemotherapy (OR 1.97, P = .07). For ASCO-CRC a non-significant association in the opposite direction was observed (OR 0.40, P = .06). Conclusions: Clinical benefit scales can be sensitive to the type of control group therapy. RCTs with an active treatment and matched placebo in the control group were less likely to be scored as providing substantial clinical benefit using the ESMO-MCBS and the ASCO-VF scales. Control group therapy did not influence NCCN Evidence Blocks or ASCO-CRC scores.

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.

IMPORTANCE The high cost of cancer medicines is a public health challenge. Policy makers in the US and Europe are debating reforms to drug pricing that would cover both the prices of new medicines when entering the market and price increases after they are launched. OBJECTIVE To assess launch prices, postlaunch price changes, and clinical benefit of cancer drugs in the US compared with 3 European countries (England, Germany, and Switzerland). DESIGN, SETTING, AND PARTICIPANTS This economic evaluation identified all new drugs that were approved for use in the US, England, Germany, and Switzerland with initial indications for treatment of adult solid tumor and hematologic cancers. Analysis included drugs approved by the US Food and Drug Administration between January 1, 2009, and December 31, 2019, and by the European Medicines Agency and Swissmedic until December 31, 2019. Prices were adjusted for currency and inflation. Clinical benefit of drugs indicated for solid tumors was assessed using the American Society of Clinical Oncology Value Framework and European Society for Medical OncologyMagnitude of Clinical Benefit Scale. Using Spearman rank correlation coefficients, correlations between clinical benefit and launch prices and postlaunch price changes for each country were evaluated. MAIN OUTCOMES AND MEASURES Launch prices, postlaunch price changes, and clinical benefit of cancer drugs. RESULTS The cohort included 65 drugs: 47 (72%) approved for solid tumors and 18 (28%) for hematologic cancers. In all countries, the lowest median monthly treatment costs at launch were greater in 2018-2019 vs 2009-2010: $14 580 vs $5790 in the US, $5888 vs $4289 in Germany, $6593 vs $5784 in Switzerland, and $6867 vs $3939 in England. Between 2009 and 2019, 48 of 65 (74%) cancer drugs had price increases in the US that were greater than inflation. Only 1 of 62 (2%) drugs in England, 0 of 60 drugs in Germany, and 7 of 56 drugs (13%) in Switzerland had a median price increase greater than inflation. There were no associations between launch prices or postlaunch price changes and clinical benefit in any assessed country. CONCLUSIONS AND RELEVANCE During this economic evaluation study period, launch prices of cancer drugs were substantially higher in the US than in the assessed similar high-income European countries, a gap that increased in the years after approval. Cancer drug prices frequently increased faster than inflation in the US but decreased on inflation-adjusted terms in Europe. Price changes were not associated with clinical benefit in any country.

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.

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.

Background Clinical practice guidelines (CPGs) are crucial to the practice of evidence-based medicine. Declared author financial conflicts of interest (FCOIs) are common in CPGs and have been associated with endorsement of treatment. Less is known about undeclared FCOIs. Methods The American Society of Clinical Oncology (ASCO) website was searched to identify all CPGs for systemic therapy published between August 2013 and June 2018. Data on self-reported author FCOIs and funding sources were extracted. The Open Payments database was then searched to identify compensation to CPG authors. Concordance between declared and undeclared but verified FCOIs was assessed with Cohen's kappa. Results For 26 CPGs, 314 nonduplicate authors were identified; 184 of these authors (59%) disclosed FCOIs. Among the remaining 130 authors, data in Open Payments were unavailable for 71 authors (non-US residents or authors affiliated with a nonprofit organization). Among the 59 authors who declared no FCOIs and for whom Open Payments data were available, 55 (93%) had received payment from industry. The kappa value for agreement between disclosed and verified FCOIs was 0.092. Among the 243 authors with FCOIs verifiable via Open Payments, 239 (98%) received payment from industry. Thirty-four authors (62%) received more than $1000 in nonresearch funding, and 19 (35%) received more than $5000. Among the 52 first and last authors, 44 (85%) received payment from industry; 14 of these payments (32%) were not declared. Conclusions FCOIs among authors of ASCO CPGs are common and are not disclosed by a substantial proportion of authors with Open Payments data. Improved transparency of FCOIs should become standard practice among CPG authors. Professional societies and journal editors need to create a mechanism to verify self-reported FCOIs.

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.

7052 Background: Initial drug approval is often based on surrogate endpoints. Definitive outcomes like Overall Survival (OS) or Quality of life (QoL) may not be available. Here, we evaluate changes in the magnitude of clinical benefit using the American Society of Clinical Oncology Value Framework (ASCO-VF) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) comparing the time of approval to the most recent available data for cancer drugs approved by the US Food and Drug Administration (FDA) between 2006 and 2015. Methods: We examined data on trials supporting FDA accelerated (AA) and regular (RA) cancer drug approvals between January 2006 and December 2015. We performed a systematic search of Pubmed and ClinicalTrials.gov to identify updated OS and/or QoL data, with follow up through April 2019. For AA drugs we analysed initial and confirmatory trials as follow-up. ASCO-VF and ESMO-MCBS grades were applied for trials at approval and after marketing. We explored variables associated with improved clinical benefit scores using multivariable logistic regression. Results: We identified 102 trials supporting the approval of 59 drugs for 96 solid tumour indications. Of these indications, 22 (23%) were granted AA and 21 (95%) were converted to RA. At time of approval, 38% of trials showed improved OS and 17% improved QoL. Substantial clinical benefit was observed in 26% of initial approval trials using ESMO-MCSB and in 34% using ASCO-VF. After a median post-marketing period of 3.3 years, updated results changed substantial clinical benefit in 20 trials with ESMO-MCBS (19 upgrades, 1 downgrade) and in 23 trials using ASCO-VF (19 upgrades, 4 downgrades). For 25% of trials no updated information was found. In the palliative setting, multivariable analysis showed association between improved ASCO-VF scores and initial approvals based on single-arm trials (OR 9.21, 95%CI 1.36-62.29, P=0.023), drugs with companion diagnostics (OR 4.95, 95%CI 1.01-24.22, P=0.049) and second or later lines (OR 7.80, 95%CI 1.35-45.02, P=0.022) while for ESMO-MCBS, drugs with companion diagnostics (OR 6.86, 95%CI 1.82-25.86, P=0.004) and immunotherapy drugs (OR 6.42, 95%CI 1.27-32.59, P=0.025) were associated with greater clinical benefit. Conclusions: Drugs with companion diagnostic tests, immunotherapy as well as approved based on single-arm trials were associated with increased clinical benefit after marketing approval. For a quarter of trials there were no updated data in the post-marketing period.

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.

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.

This study uses the European Society of Medical Oncology Magnitude of Clinical Benefit Scale to evaluate the clinical benefit of anticancer drugs that gained approval by the US Food and Drug Administration based on single-arm rather than randomized clinical trials.

6513 Background: The Breakthrough Therapy program was established in July 2012 to expedite drug development and approval by the FDA. We compared the characteristics of clinical trials leading to FDA approval as well as the magnitude of clinical benefit and value framework scores of breakthrough-designated and non-breakthrough-designated cancer drugs. Methods: We searched the Drugs@FDA website for cancer drug approvals from July 2012 and December 2017. For each indication, we applied the value frameworks and used thresholds of high clinical benefit developed by American Society of Clinical Oncology Value Framework version 2 (ASCO VF v2; scores ≥45), the ASCO Cancer Research Committee (OS gains ≥2.5 months PFS gains ≥3 months), the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1; grade of A or B for trials of curative intent and 4 or 5 for those of non-curative intent), and the National Comprehensive Cancer Network (NCCN) Evidence Blocks (scores of 4 and 5). Trial characteristics and value framework scores were compared using Chi squared or Mann Whitney U tests. Results: We identified 106 pivotal trials supporting the approval of 52 individual drugs for 96 indications. Of these indications, 38 (40%) received breakthrough designation. Compared with trials for non-breakthrough drugs (n = 62), trials for breakthrough drugs (n = 44) had smaller sample size (median 373 vs 612, P= .03), were less often randomized (57% vs 86%; P= .001) and more likely to be open-label (84% vs 53%, P= .001). Trials for breakthrough drugs were more likely to demonstrate high clinical benefit using ASCO VF (68% vs 31%, P= .002) and NCCN Evidence Blocks (86% vs 56%, P= .002). A similar proportion of trials supporting breakthrough and non-breakthrough drugs demonstrated high clinical benefit using the ASCO Cancer Research Committee (82% vs 68%, P= .25) and ESMO-MCBS (35% vs 33%; P= .87) frameworks. Conclusions: In patients with advanced solid tumors, cancer drugs approved under breakthrough therapy designation were more likely to demonstrate high clinical benefit as defined by the ASCO VF and NCCN value frameworks. A similar proportion of approved breakthrough and non-breakthrough therapy drugs met the high benefit thresholds using the ASCO Cancer Research Committee and ESMO-MCBS frameworks.

6638 Background: Given rising cancer drug costs, Medicare recently proposed to tie some US 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 selected 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 included European countries were 52% (interquartile range: 37-72%) lower than US prices. There was no statistically significant 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: Cancer drug prices in the US were significantly higher than in the compared European countries. Drug prices of cancer drugs were not associated with clinical benefit in the US or in European countries.

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.

Purpose Clinical practice guidelines (CPGs) and consensus statements (CSs) are used to apply evidence-based medicine or expert recommendations to clinical practice. Here we explore author financial conflicts of interest (FCOIs), sources of guideline funding, and their relationship with endorsement of specific drugs. Methods An electronic search of MEDLINE was conducted to identify CPGs and CSs for common solid cancers published between January 2003 and October 2013. The search was restricted to articles evaluating systemic therapy. We extracted data on self-reported author FCOIs, funding sources, use of manuscript writers, and endorsement of specific drugs in the abstract of the article. Results Of 142 articles evaluated, 64% were CPGs, and 36% were CSs. The proportion of articles reporting FCOIs improved from 11% in 2003 to 93% in 2013 (P for trend < .001). Only 45% of articles explicitly reported funding sources. Of these, 65% disclosed partial or full industry sponsorship. Use of manuscript writers was declared in 13%, but many articles did not explicitly report the role of authors in the writing of the manuscript. Endorsement of specific drugs was significantly associated with author FCOIs (odds ratio [OR], 7.29; P = .001), but not with industry funding (OR, 0.95; P = .37). Conclusion Reporting of FCOIs in CPGs and CSs has improved over time. Despite prevalent funding of guideline development by industry, such funding is not associated with endorsement of specific drugs. Author FCOIs are prevalent, and endorsement of a specific drug seems to be more common when authors have FCOIs with the pharmaceutical company marketing that drug.

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.

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.

IMPORTANCE The US Food and Drug Administration (FDA) advisory committees influence decisions relating to the regulatory approval of drugs in the United States. Outside of the field of oncology, prosponsor voting bias has been observed among members with financial conflicts of interest (FCOIs). OBJECTIVE To explore factors associated with Oncologic Drugs Advisory Committee (ODAC) recommendations and the influence ODAC members' FCOIs on the drug approval process. DESIGN, SETTING, AND PARTICIPANTS Retrospective analysis of 82 ODAC meeting transcripts between January 2000 and December 2014. Analysis was restricted to meetings at which votes were cast relating to oncologic drugs. The influence of methodology of trials supporting approval and frequency and type of self-reported FCOIs of voting members was explored using logistic regression. MAIN OUTCOMES AND MEASURES ODAC recommendation for drug approval and subsequent FDA approval. RESULTS Eighty-two transcripts of ODAC meetings between January 2000 and December 2014 were available for analysis. During the time period analyzed, ODAC members voted on 68 applications in 79 meetings (the remaining 3 meetings included voting questions regarding postmarketing safety or trial design). There was agreement between ODAC recommendations and final FDA approval; FDA approval was received for all 41 drugs that ODAC recommended approval. Additionally, the FDA approved 7 out of 41 agents that were not recommended for approval by ODAC (kappa = 0.83). In 51 of 79 meetings, more than 1 trial was available to support the indication of a particular drug, and favorable ODAC recommendations were more likely when this was the case (odds ratio [OR], 1.82; 95% CI, 1.19-2.78; P = .01). Availability of randomized data did not appear to be important with selected single-arm phase 2 trials leading to recommendations for approval, especially in rare diseases. There has been a significant reduction in FCOIs over time (31 of 77 voting members [40%] in 2000 vs 0 of 20 voting members in 2014 [0%]; P < .001). Recommendations for approval were made in 28 of 47 meetings with members reporting FCOIs while among meetings with no reported FCOIs, recommendations for approval were made in 13 of 35 meetings (OR, 1.19; 95% CI, 0.97-1.46; P = .10). No significant association between ODAC recommendations and FDA approval was observed for members with FCOIs with the sponsor (OR, 1.79; 95% CI, 0.97-1.46; P = .19 and OR, 3.48; 95% CI, 0.84-14.35; P = .09, respectively) compared with members with FCOIs with competitors (OR, 1.06; 95% CI, 0.78-1.44; P = .72 and OR, 0.94; 95% CI, 0.69-1.28; P = .69, respectively). CONCLUSIONS AND RELEVANCE Availability of multiple trials is associated with higher odds of ODAC recommendation and drug approval. Availability of randomized data appears less important. Declaration of FCOIs among ODAC members was frequent during the time period of interest but has decreased significantly over time. There is no apparent association between FCOIs and ODAC recommendations and subsequent FDA approval.

6582 Background: FDA advisory committees influence decisions relating to the regulatory approval of drugs in the United States. Little is known about whether ODAC members’ FCOIs affect the FDA’s on...

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).

10555 Background: There is growing evidence that topoisomerase II-alpha (TOPOIIα) is a marker for anthracycline-, and microtubule-associated protein tau (MAPT) for taxane sensitivity. HER2 has been described as a marker of both anthracycline and taxane sensitivity.The goal of our study was to examine the predictive and prognostic value of TOPOIIα, MAPT and HER2 expression in breast cancer patients (pts) who received neoadjuvant chemotherapy (NAC) based on anthracycline-taxane regimens. We analyzed the relationship between these biomarkers and pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). Methods: Between November 1993-2009, 140 pts (mean age 52 years) with locally advanced breast cancer (T1-4, N0-3, M0) were retrospectively studied. The study contained 2 groups: group A included 85 pts who received NAC with an anthracycline-taxane regimen and group B included the last 55 pts who received NAC with only an anthracycline-based regimen. HER2 was tested by immunohistochemistry (IH) or FISH, TOPOIIα by CISH and MAPT by IH. Expression of these proteins was evaluated in core needle breast biopsy. Results: Overall, 12 pts (8.5%) had a pCR. TOPOIIα was amplified in 6 (4%) of the tumors. Among pts without amplification, 6 (4%) had deletion of the TOPOIIα, and 10 (7%) polysomia of chromosome 17. TOPOIIα gene aberrations (amplification, deletion, polysomia), which was present in 22 (25%) of the tumors, was a strong predictive factor for pCR (p=0.018) but showed no direct association with prognostic outcome in multivariate analysis. HER2 amplification, which was present in 16% (21) of the tumors, show no direct association with pCR, DFS or OS. Finally, differences by treatment arm or pCR in low versus high MAPT expression groups were not observed, indicating that MAPT is not a useful predictive marker for taxane-based chemotherapy. In multivariate analysis high MAPT expression was associated with longer DFS (p=0.002). Conclusions: TOPOIIα gene aberrations but not HER2 are highly predictive of pCR for anthracycline-based regimen. MAPT is not associated with response to taxanes but has a prognostic value.

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.

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...