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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.

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.

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.