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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: 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.

CONSORT DIAGRAM

Purpose: We previously detected promising efficacy of neoadjuvant nintedanib (a multityrosine kinase inhibitor, TKI) in early HER2-negative breast cancer. In a preclinical study, we monitored stromal hypoxia with 18F-fluoromisonidazole-positron emission tomography (18F-FMISO-PET); we found that reoxygenation of tumors (or lack of it) during a window-of-opportunity (WoO) treatment with TKIs correlated with the benefit (or lack of it) from TKI-plus-chemotherapy combinations. We studied the predictive role of 18F-FMISO-PET for the TKI nintedanib in the neoadjuvant setting in a phase II WoO randomized trial.Experimental Design: Patients were randomized to a 14-day WoO of nintedanib preceded and followed by an 18F-FMISO-PET, followed by nintedanib plus weekly paclitaxel (Arm A) or an 18F-FMISO-PET followed by weekly paclitaxel (Arm B) before surgery. The endpoint was residual cancer burden (RCB). The objective was to detect the patients with no response (RCB-III) on the basis of the baseline or evolutive 18F-FMISO-PET values/changes.Results: One-hundred and thirty HER2-negative patients were randomized. Seventeen (27.9%), 34 (55.7%), and 8 (13.1%) patients had an RCB of III, II, and I/0, respectively, in Arm A. In this arm, baseline hypoxic tumors had a 4.4-fold higher chance of experiencing RCB = 3 (P = 0.036) compared with baseline normoxic tumors. Nintedanib WoO induced tumor reoxygenation in 24.5% of the patients; those not reoxygenating showed a trend toward higher chance of experiencing RCB-III (6.4-fold; P = 0.09). In Arm B, 18F-FMISO-PET lacked predictive/prognostic value.Conclusions: Baseline hypoxic tumors (measured with 18F-FMISO-PET) do not benefit from neoadjuvant nintedanib. Clin Cancer Res; 23(6); 1432–41. ©2016 AACR.

Figure S1 legend

Hypoxic volumes

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: The incidence of breast cancer brain metastases (BCBM) is estimated to be around 5-15%, but necropsies show a much higher incidence (30-50%). Frecuency of BCBM has gradually increase likely as a result from advances in systemic treatment that allow more patients to live long enough to develop BCBM. In general, outcome for patients with BCBM is poor, with 1-year survival of approximately 20%, but some patient and tumor characteristics are associated with improved behaviour. The RegistEM study is a non-interventional cohort study providing prospective data from around 1,867 advanced breast cancer (ABC) patients (pts.). This study offers a unique opportunity to assess the incidence, potential risk factors, and outcomes for patients with BCBM. Methods: In this analysis (cut-off date 26/April/2021 and ongoing database), we describe the features of 218 pts. with BCBM included in the RegistEM study, which represent the 11% of current total number of pts. in the study. BC clinical subtypes are based on the most recent tumor lesion (distant metastasis or primary BC). The most frequent therapies by BC subtypes are detailed in the table below. At the database cut-off date, death had been reported in 74% pts with BCBM. Results: All pts. were female, 97% caucasian, and at ABC diagnosis, 66% were postmenopausal and their median age was 55 years. The subtype distribution was: Luminal (ER+/HER2-) 41%, HER2+ 35%, Triple Negative (TN) 19%, unknown 5%. Eighty pts. (37%) had BM at diagnosis of ABC, and in 17 of them BM was the only site of relapse. The median time from diagnosis of primary BC to BM at initial diagnosis of ABC was 34 months (mo), being shorter for TN (18 mo). In patients without BM at diagnosis of ABC, the median time from ABC diagnosis to onset of BM for de novo metastatic disease was: Luminal 27 mo, HER2+ 28 mo, TN 10 mo; while for EBC disease was: Luminal 18 mo, HER2+ 14 mo, TN 10 mo. De novo metastatic BC was associated with longer time to BM appearance (HR:0.527, CI 95%: 0.358-0.776) while TN subtype with shorter time (HR:4.122, CI 95%: 2.318-7.329) compared to Luminal subtype. The median survival from the onset of BM, according to BC subtype was: Luminal 6 mo, HER2 11 mo and TN 4 mo. Risk factors for worse survival were: BM at ABC (HR:1.677, CI 95%:1.169-2.406) and TN subtype (HR:3.631, CI 95%: 2.353-5.603) compared to Luminal subtype. Conclusions: TN breast cancer is associated with a shorter time to brain metastases and poorer outcome than other breast cancer subtype. Patients with de novo metastatic BC develop metastases later than patients with metastatic recurrence after primary BC. New treatment approach to avoid the onset of brain metastases in patients with ABC warrants further research. Luminaln=90 (41%)HER2+n=77 (35%)Triple Negativen=41 (19%)HRHER2+-Any+–First BC diagnosis, nEBC (stages I-III)ULABC or de novo metastatic65. 2555. 2227. 14Only CNS metastases at ABC diagnosis584Number of line (L)1L2L3L1L2L3L1L2L3Ln877158745936352515Type of therapy, nET/BT26167443---ET239531----CT/BT/ET58-15-----CT/BT10924014211331CT/ET623------CT172635321222214BT1693811---Most frequent therapies by mechanism of action, nAI/CDK4/6i 20SERD 12CT single agent 12AI single agent 11CT + antiangiogenic 9CT single agent 24SERD +/- CDK4/6i 8AI + CDK4/6i 7CT + antiangiogenic 7CT single agent 27CT combination 8SERD +/- CDK4/6i 6CT + dual anti-HER2 blockade 46CT + anti-HER2 blockade single agent 7Anti-HER2 single agent 35CT + anti-HER2 blockade single agent 12CT + anti-HER2 blockade single agent 18Anti-HER2 blockade single agent 9CT combination 12CT + antiangiogenic 12CT single agent 10CT single agent 16CT combination 6CT + antiangiogenic 4CT single agent 9CT combination 5Median Treatment duration, months (range)7 (0-31)6 (0-41)4 (0-16)12 (0-43)5 (0-47)3 (0-17)5 (0-18)3 (0-7)2 (0-6)TTP in months, median (range)8 (2-35)--12 (3-46)--6 (2-19)--Death, n635139Abbreviations: HR=hormone receptor; HER2=human epidermal growth factor receptor 2; BC=breast cancer; EBC=early breast cancer; ULABC=unresectable locally advanced breast cancer; ET=endrocrine therapy; BT=biological therapy; CT=chemotherapy; TTP=time to progression; AI=aromatase inhibitor; SERD=selective estrogen receptor degrader; CDK4/6i=cyclin dependent kinases 4 and 6 inhibitor Citation Format: Sara López-Tarruella, Ángel Guerrero-Zotano, César A Rodríguez, Josefina Cruz, María Hernández, Encarna Adrover, Álvaro Rodríguez-Lescure, Catalina Falo, Purificación Martínez, Ana Miguel, Raquel Andrés, Silvia Antolín, J. Ignacio Chacón, Jose Luis Alonso Romero, Rafael Villanueva Vázquez, Ana Isabel Ballesteros García, María Galán Gramaje, Diego Malón Jiménez, Silvia Varela Ferreiro, Diana Moreno Muñoz, Ruth Campo, María José Escudero, Susana Bezares, Federico Rojo, Isabel Alvarez. Breast cancer clinical subtypes in brain metastases patients from a prospective registry of advanced breast cancer, 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 PD4-08.

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.

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 is a non-interventional cohort study enrolling 1,867 patients (pts) (males or females) with advanced breast cancer diagnosed from January 2016 to December 2019, either after recurrence or as first diagnosis, in 38 Spanish sites. Triple negative BC (TNBC) is clinically defined based on lack of expression of both estrogen and progesterone receptors, and HER2 overexpression, and constitutes approximately 16% of BC cases. It is a particularly proliferative and aggressive BC subtype characterized by higher rates of relapse, greater metastatic potential, and shorter overall survival compared with other BC subtypes. Recent studies have shown hormone receptor status can change from the primary (P) to the recurrence tumor (M) in a proportion of cases, inducing a switch to TNBC in the recurrence, while other remains TNBC both in the P and M setting. This feature might impact survival and treatment options. Methods: We selected TNBC pts from the RegistEM study with ctDNA plasma samples available from the relapse. TNBC pts were classified into 2 groups according to clinical subtype (CS): 1) CS-converted (CS-C), with a discordant phenotype (TN subtype in M but not in P); and 2) CS-non-converted (CS-NC), with TN phenotype in P and M. To compare the mutation profiles of the 2 groups, next-generation sequencing (NGS) was performed using the AVENIO Expanded ctDNA Analysis Kit (Roche Sequencing Solutions, Inc; 77 genes; SNPs, indels, fusions and CNVs). Genomics alterations at individual level and grouped by pathway were explored for pathogenic and probably pathogenics variants. Genomics findings were correlated with clinicopathological data and outcomes, in terms of progression-free survival (PFS) and response to first line chemotherapy treatment. Kaplan-Meier estimator and Cox regression model were used to analyze PFS, and Fisher’s test to analyze contingency tables. Bonferroni correction was used for multiple testing. Results: NGS data was available from 32 (17%) TNBC pts; 22 (69%) pts CS-NC and 10 (31%) CS-C. The time from diagnosis to relapse was 29.2 months (m) for CS-NC and 60.2m for CS-C (HR=4.81, 95% confidence interval (CI) (1.59-14.59), p=0.0055; adjusted for confounders: menopausal status, grade, stage). In the metastatic setting, CS-NC had similar PFS than CS-C (8.3m CS-C vs 5.3m CS-NC; HR=1.63, 95% CI (0.71-3.72), p=0.2442). A median of 3 genomic alterations were found, similar in both groups. The most frequent somatic alterations were TP53 (50%), MAP2K1 (25%) and APC (25%). CS-C were enriched for MAP2K1 (60% vs. 9% in CS-NC; p=0.0243). No single genomic alteration was associated with outcome. Forty-percent of tumors harbored at least 1 mutation in PI3K-AKT-mTOR pathway (PIK3CA, PIK3R1, AKT1, AKT2, PTEN or MTOR genes), with similar incidence between CS-NC and CS-C. Pts with an altered PI3K-AKT-mTOR pathway had poor PFS (3.9m mutant vs 6.7m wild-type (WT); HR=3.02, 95% CI (1.4-6.56), p=0.0033) and a trend to worse response (complete or parcial response and stable disease: 23% mutant vs 77% WT, p=0.1581). CS-C tumors presented an altered MAPK-ERK pathway (mutations in KRAS, NRAS, BRAF, MAP2K1 or RAF1 genes) more frequently in comparison to CS-NC (60% vs 23%, p=0.0557), with no differences in response or PFS. Finally tumors with a high mutation allele frequency (≥mean) showed poor PFS (HR=3.64, 95% CI (1.52-8.75), p=0.0038). Conclusion: Analysis of ctDNA reveals diverse mutational spectrum in metastatic TNBC, suggesting that the presence of PI3K-AKT-mTOR pathway alterations associates with worse outcome and poor response to standard therapies. The clinical subtype conversions from luminal primary tumor are enriched in MAPK-ERK pathway alterations. Citation Format: Angel Guerrero-Zotano, Carlos Jara, Sara López-Tarruella, César A Rodríguez, Encarna Adrover, Catalina Falo, Purificación Martínez, Silvia Antolín, Mireia Margeli, Josefina Cruz, Alvaro Rodríguez-Lescure, Vega Iranzo, César Gómez-Raposo, Jose Juan Illarramendi, Diego Malón, Jose Luis Alonso, Antonio Antón, Raquel Andrés, Jesús Herranz, Susana Bezares, Rosalía Caballero, Isabel Álvarez, Federico Rojo. Mutational profile from circulating tumor DNA in triple negative breast cancer: Results from the 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 PS5-22.

This study evaluates the impact of breast cancer (BC) in health related quality of life (HRQL) and in psychological distress (PD) during the initial phases of the disease and looks for contributing factors. A multicentric case-control study, EpiGEICAM, was carried out. Incident BC cases and age- and residence- matched controls were included. Clinical, epidemiological, HRQL (SF-36) and PD information (GHQ-28) was collected. We used multivariable logistic regression models to estimate OR of low HRQL and of PD in cases compared to controls, and to identify factors associated with low HRQL and with PD. Among 896 BC cases and 890 control women, cases had poorer scores than both, the reference population and the control group, in all SF-36 scales. BC women with lower education, younger, active workers, never smokers, those with comorbidities, in stage IV and with surgical treatment had lower physical HRQL; factors associated with low mental HRQL were dissatisfaction with social support, being current smoker and having children. Cases had a fivefold increased odds of PD compared to controls. Managing comorbidities and trying to promote social support, especially in younger and less educated women, could improve well-being of BC patients., This study was supported by Fundación Científica Asociación Española Contra el Cáncer (AECC) (Scientific Foundation of the Spanish Association Against Cancer), Fundación Cerveza y Salud 2005 (Beer and Health Foundation 2005), Sociedad Española de Oncología Médica (SEOM) (Spanish Society of Medical Oncology), Ministerio de Economía y Competitividad (Spanish Ministry of Economy and Competitiveness, IJCI-2014–20900), and Federación Española de Cáncer de Mama (FECMA) (Spanish Federation of Breast Cancer)

Purpose: We previously detected promising efficacy of neoadjuvant nintedanib (a multityrosine kinase inhibitor, TKI) in early HER2-negative breast cancer. In a preclinical study, we monitored stromal hypoxia with 18F-fluoromisonidazole-positron emission tomography (18F-FMISO-PET); we found that reoxygenation of tumors (or lack of it) during a window-of-opportunity (WoO) treatment with TKIs correlated with the benefit (or lack of it) from TKI-plus-chemotherapy combinations. We studied the predictive role of 18F-FMISO-PET for the TKI nintedanib in the neoadjuvant setting in a phase II WoO randomized trial. Experimental Design: Patients were randomized to a 14-day WoO of nintedanib preceded and followed by an 18F-FMISO-PET, followed by nintedanib plus weekly paclitaxel (Arm A) or an 18F-FMISO-PET followed by weekly paclitaxel (Arm B) before surgery. The endpoint was residual cancer burden (RCB). The objective was to detect the patients with no response (RCB-III) on the basis of the baseline or evolutive 18F-FMISO-PET values/changes. Results: One-hundred and thirty HER2-negative patients were randomized. Seventeen (27.9%), 34 (55.7%), and 8 (13.1%) patients had an RCB of III, II, and I/0, respectively, in Arm A. In this arm, baseline hypoxic tumors had a 4.4-fold higher chance of experiencing RCB = 3 (P = 0.036) compared with baseline normoxic tumors. Nintedanib WoO induced tumor reoxygenation in 24.5% of the patients; those not reoxygenating showed a trend toward higher chance of experiencing RCB-III (6.4-fold; P = 0.09). In Arm B, 18F-FMISO-PET lacked predictive/prognostic value. Conclusions: Baseline hypoxic tumors (measured with 18F-FMISO-PET) do not benefit from neoadjuvant nintedanib. Clin Cancer Res; 23(6); 1432–41. ©2016 AACR.

Purpose Capecitabine is an active drug in metastatic breast cancer (BC). GEICAM/2003-10 is an adjuvant trial to investigate the integration of capecitabine into a regimen of epirubicin and docetaxel for node-positive early BC. Patients and Methods Patients with operable node-positive BC (T1-3/N1-3) were eligible. After surgery, 1,384 patients were randomly assigned to receive epirubicin plus cyclophosphamide (EC; 90 and 600 mg/m2, respectively, × four cycles), followed by docetaxel (100 mg/m2 × four cycles; EC-T) or epirubicin plus docetaxel (ET; 90 and 75 mg/m2, respectively, × four cycles), followed by capecitabine (1,250 mg/m2 twice a day on days 1 to 14, × four cycles; ET-X); all regimens were given every 3 weeks. The primary end point was invasive disease-free survival. Secondary end points included safety (with an alopecia-specific study) and overall survival (OS). Results After a median follow-up of 6.6 years and 297 events, 86% of patients who received EC-T and 82% of those who received ET-X were invasive disease free at 5 years (hazard ratio, 1.30; 95% CI, 1.03 to 1.64; log-rank P = .03). The OS difference between arms was not statistically significant (hazard ratio, 1.13; 95% CI, 0.82 to 1.55; log-rank P = .46). The most frequent grade 3 to 4 adverse events in the EC-T versus ET-X arms were neutropenia (19% v 10%), with 7% febrile neutropenia across arms; fatigue (13% v 11%); diarrhea (3% v 11%); hand-foot syndrome (2% v 20%); mucositis (6% v 5%); vomiting (both, 5%); and myalgia (4.5% v 1%). Incomplete scalp hair recovery was more frequent in the EC-T than ET-X arm (30% v 14%), and patients who received EC-T wore wigs significantly longer than those who received ET-X (8.35 v 6.03 months). Conclusion Invasive disease-free survival, but not OS, was significantly superior for patients with node-positive early BC who received the adjuvant standard schedule EC-T than for those who received the experimental ET-X regimen. Toxicity profiles differed substantially across arms.

Introduction: Retrospective data from institutional series and population-based databases have suggested a potential benefit of the primary tumor (PT) surgery in de novo metastatic breast cancer (MBC) patients (pts). Recently reported prospective data from 2 randomized trials and a multicenter registry questioned the real role of the local approach in the modern individualized systemic treatment era. Methods: The ALAMO (A) is a retrospective analysis of pts diagnosed with BC between 1990 and 2001 across 56 GEICAM hospitals in Spain. Patterns of BC presentation (tumor and host characteristics), treatment and survival were recorded in 3 cohorts, AI (1990-93, 4529 pts, closed by 2000), AII (1994-97, 10453 pts, closed by 2003) and AIII (1998-2001, 10675 pts, closed by 2007). MBC pts at first diagnosis excluding those without complete information about their PT surgery were included. Descriptive, Kaplan-Meier and Cox regression analyses were carried out. Results: 5.5% (N=1415) of the ALAMO database pts were initially diagnosed with MBC, 1331 fulfilled the present analysis criteria (327 from AI, 619 from AII and 385 from AIII). Median age was 63.1 years (range: 21.6-96.0), 51.8% had single-organ metastasis, and their distribution according to the predominant site of disease was skin/soft tissue (16.2%), bone (33.7%), and visceral (48.4%). Surgery of the PT was done in 44.5% (N=592) of pts (512 with radical procedures, 46 with palliative procedures and 34 unknown); besides, 427 pts underwent axillary dissection. Initial local treatment was the choice for 380 pts (358 surgery and 22 radiotherapy), 722 received initial systemic therapy (480 chemotherapy, 214 endocrine treatment and 28 both), 29 received best supportive care and for 200 pts the treatment sequence could not be established. Pts in the surgery (S) group were younger (19.5% vs 11.8% were Citation Format: Sara López-Tarruella, María José Escudero, Miguel Martín, Carlos Jara, Ángel Guerrero, Ana Lluch, Ana Santaballa, Purificación Martínez del Prado, Juan Lao, Emilio Alba, Antonio Fernández, Raquel Andrés, Antonio Llombart, Norberto Batista, Ignacio Porras, José Manuel López-Vega, Encarna Adrover, Lourdes Calvo, Marina Pollán, Eva Carrasco. Impact on survival of primary tumor resection in women with de novo metastatic breast cancer. The GEICAM Alamo I-III breast cancer registry (1990-2001) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-13-17.

Resumen A pesar del aumento en la prevalencia del cancer de mama, el seguimiento de estas pacientes no esta totalmente estandarizado. La Sociedad Espanola de Senologia y Patologia Mamaria propuso la elaboracion de un documento de consenso sobre el seguimiento que deberia proponerse a las pacientes afectas de lesiones de mama in situ e infiltrantes en estadios i - iii , tratadas con intencion curativa, una vez finalizados los tratamientos iniciales. En su realizacion han colaborado profesionales de toda Espana de distintas especialidades y ambitos de actuacion. Fue presentado en el Primer Congreso Espanol de la Mama, que se celebro en octubre de 2013 en Madrid, para su refrendo por parte de la Sociedad, y se recogieron las aportaciones de los asistentes a la sala. El objetivo principal del seguimiento es la deteccion precoz de recurrencias locorregionales y a distancia, de nuevos primarios, y valorar los efectos secundarios de los tratamientos aplicados. Debe tambien cubrir las necesidades de soporte psicologico, asi como la rehabilitacion y reinsercion sociolaboral posterior y la educacion para la salud, corrigiendo habitos de vida no saludables. No se han descrito diferencias significativas entre el seguimiento minimalista y el intensivo, respecto al indice de recurrencia, la supervivencia global y la calidad de vida. El tipo y los anos de seguimiento deberian ser distintos para cada paciente segun su riesgo de recidiva y la clasificacion molecular de su lesion. Este consenso ha tenido el apoyo de otras sociedades cientificas relacionadas con la enfermedad mamaria, asistentes al Primer Congreso Espanol de la Mama.

ObjectivePatients' psychological reactions to multigene cancer panel testing might differ compared with the single-gene testing reactions because of the complexity and uncertainty associated with the different possible results. Understanding patients' preferences and psychological impact of multigene panel testing is important to adapt the genetic counselling model. MethodsOne hundred eighty-seven unrelated patients with clinical suspicion of hereditary cancer undergoing a 25-gene panel test completed questionnaires after pretest genetic counselling and at 1week, 3 months, and 12months after results to elicit their preferences regarding results disclosure and to measure their cancer worry and testing-specific distress and uncertainty. ResultsA pathogenic variant was identified in 38 patients (34 high penetrance and 4 moderate penetrance variants), and 54 patients had at least one variant of uncertain significance. Overall, cancer panel testing was not associated with an increase in cancer worry after results disclosure (P value=.87). Twelve months after results, carriers of a moderate penetrance variant had higher distress and uncertainty scores compared with carriers of high penetrance variants. Cancer worry prior to genetic testing predicted genetic testing specific distress after results, especially at long term (P value

// Miguel Quintela-Fandino 1 , Nora Soberon 2 , Ana Lluch 3 , Luis Manso 4 , Isabel Calvo 5 , Javier Cortes 6, 7 , Fernando Moreno-Anton 8 , Miguel Gil-Gil 9 , Noelia Martinez-Janez 7 , Antonio Gonzalez-Martin 10 , Encarna Adrover 11 , Raquel de Andres 12 , Gemma Vinas 13 , Antonio Llombart-Cussac 14 , Emilio Alba 15 , Silvana Mouron 1 , Juan Guerra 16 , Begona Bermejo 3 , Esther Zamora 6 , Jose Angel Garcia-Saenz 8 , Sonia Pernas Simon 9 , Eva Carrasco 17 , Maria Jose Escudero 17 , Ruth Campo 17 , Ramon Colomer 18 , Maria A. Blasco 2 1 Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Madrid, Spain 2 Telomeres and Telomerase Group, Molecular Oncology Programme, CNIO-Spanish National Cancer Research Center, Madrid, Spain 3 Medical Oncology Department, Hospital Clinico Universitario, Valencia, Spain 4 Medical Oncology Department, Hospital 12 de Octubre, Madrid, Spain 5 Medical Oncology Department, Hospital de Monteprincipe, Madrid, Spain 6 Medical Oncology Department, Hospital Vall d´Hebron, Barcelona, Spain 7 Medical Oncology Department, Hospital Ramon y Cajal, Madrid, Spain 8 Medical Oncology Department, Hospital Clinico San Carlos, Madrid, Spain 9 Medical Oncology Department, Institut Catala d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain 10 Medical Oncology Department, MD Anderson Cancer Center, Madrid, Spain 11 Medical Oncology Department, Hospital General de Albacete, Albacete, Spain 12 Medical Oncology Department, Hospital Lozano Blesa, Zaragoza, Spain 13 Medical Oncology Department, Institut Catala d'Oncologia-Hospital Dr. Josep Trueta, Girona, Spain 14 Medical Oncology Department, Hospital Arnau de Vilanova, Valencia, Spain 15 Medical Oncology Department, Hospital Clinico Universitario Virgen de la Victoria, Malaga, Spain 16 Medical Oncology Department, Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain 17 GEICAM, Madrid, Spain 18 Medical Oncology Department, Hospital Universitario La Princesa, Madrid, Spain Correspondence to: Miguel Quintela-Fandino, email: mquintela@cnio.es Maria A. Blasco, email: mblasco@cnio.es Keywords: telomere length, critically short telomeres, breast cancer, weekly paclitaxel, toxicity Received: October 25, 2016 Accepted: January 27, 2017 Published: February 21, 2017 ABSTRACT Cumulative toxicity from weekly paclitaxel (myalgia, peripheral neuropathy, fatigue) compromises long-term administration. Preclinical data suggest that the burden of critically short telomeres ( 21.9% CSTs) had 2-fold higher number of neuropathy ( P = 0.04) or fatigue ( P = 0.019) episodes and >3-fold higher number of myalgia episodes ( P = 0.005). The average telomere length was unrelated to the incidence of side effects. The percentage of CSTs, but not the average telomere size, is associated with weekly paclitaxel-derived toxicity.

Objectives Gemcitabine has well-recognized activity in the treatment of ovarian cancer. Fixed-dose rate (FDR) delivery has been proposed as a more rationale way to administer gemcitabine, to avoid saturation of the enzyme that catalyzes its intracellular transformation into the active metabolites, difluorodeoxycitidine biphosphate, and triphosphate. Our aim was to assess clinical activity of gemcitabine delivered by FDR infusion in patients with platinum resistant ovarian cancer. Materials and methods Patients with platinum-resistant ovarian cancer received gemcitabine 1000 mg/m(2) over 120 minutes on days 1 and 8 of each cycle. Cycles were repeated every 3 weeks, and up to 6 cycles were delivered. Results Forty-eight patients were included in the study. Among 41 patients evaluable for response, 9 clinical responses (1 complete response and 8 partial responses) were observed, achieving a global response rate of 22%. Grade 3 to 4 hematological toxicity consisted of anemia (15% of patients), neutropenia (24%), and thrombopenia (10%). One patient died due to septic shock. The main grade 3 to 4 nonhematological toxicity was asthenia (7 patients, 17%). Conclusion Activity of gemcitabine administered by FDR infusion in patients with platinum-resistant ovarian cancer seems similar to that achieved using 30-minute infusions, with higher toxicity.

Clinical Trial, Phase III; Comparative Study; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov't; BACKGROUND Taxanes are among the most active drugs for the treatment of metastatic breast cancer, and, as a consequence, they have also been studied in the adjuvant setting. METHODS After breast cancer surgery, women with lymph node-positive disease were randomly assigned to treatment with fluorouracil, epirubicin, and cyclophosphamide (FEC) or with FEC followed by weekly paclitaxel (FEC-P). The primary endpoint of study-5-year disease-free survival (DFS)-was assessed by Kaplan-Meier analysis. Secondary endpoints included overall survival and analysis of the prognostic and predictive value of clinical and molecular (hormone receptors by immunohistochemistry and HER2 by fluorescence in situ hybridization) markers. Associations and interactions were assessed with a multivariable Cox proportional hazards model for DFS for the following covariates: age, menopausal status, tumor size, lymph node status, type of chemotherapy, tumor size, positive lymph nodes, HER2 status, and hormone receptor status. All statistical tests were two-sided. RESULTS Among the 1246 eligible patients, estimated rates of DFS at 5 years were 78.5% in the FEC-P arm and 72.1% in the FEC arm (difference = 6.4%, 95% confidence interval [CI] = 1.6% to 11.2%; P = .006). FEC-P treatment was associated with a 23% reduction in the risk of relapse compared with FEC treatment (146 relapses in the 614 patients in the FEC-P arm vs 193 relapses in the 632 patients in the FEC arm, hazard ratio [HR] = 0.77, 95% CI = 0.62 to 0.95; P = .022) and a 22% reduction in the risk of death (73 and 95 deaths, respectively, HR = 0.78, 95% CI = 0.57 to 1.06; P = .110). Among the 928 patients for whom tumor samples were centrally analyzed, type of chemotherapy (FEC vs FEC-P) (P = .017), number of involved axillary lymph nodes (P < .001), tumor size (P = .020), hormone receptor status (P = .004), and HER2 status (P = .006) were all associated with DFS. We found no statistically significant interaction between HER2 status and paclitaxel treatment or between hormone receptor status and paclitaxel treatment. CONCLUSIONS Among patients with operable breast cancer, FEC-P treatment statistically significantly reduced the risk of relapse compared with FEC as adjuvant therapy. Yes

This review examines all randomized studies that evaluated the role of taxanes in the neoadjuvant treatment of breast cancer and have reported results in terms of efficacy and tolerance. The primary objective of this review was to evaluate whether, at this point in time, there is sufficient evidence to support the routine use of taxanes in the neoadjuvant treatment of breast cancer. Other objectives were to determine the optimal schedule in which to administer taxanes and anthracyclines and whether the addition of other antitumor drugs improves the efficacy of these anthracycline/taxane-based schedules. A literature search revealed 9 major randomized clinical trials published to date. To facilitate analysis, they were classified according to their protocol design. Five trials evaluated the effect of the addition of a taxane to an anthracycline-based schedule, either concomitantly or sequentially. The remaining 4 trials contained taxanes in both treatment arms in an attempt to optimize the administration schedule of anthracyclines and taxanes, or to improve efficacy by adding a further antitumor drug. This type of analysis has provided the opportunity to draw some conclusions regarding the optimal use of taxanes.

Six major randomized clinical trials evaluating the role of taxanes in the adjuvant setting of breast cancer have demonstrated significant improvements in terms of efficacy in favour of the taxane treatment arm. In all cases, different anthracycline-based regimens were used as the control arm. Nevertheless, many clinicians are still not sufficiently convinced to incorporate the routine use of taxanes in the adjuvant treatment of breast cancer. There are two main objections, first the possible lack of effectiveness of chemotherapy in hormone-receptor positive tumors and second, some of the anthracycline-based control arms used in these trials were not the optimal ones. In this review, we have searched and analyzed all randomized studies that evaluated the role of taxanes in the adjuvant setting of breast cancer patients and have reported results in terms of efficacy or tolerance. The suitability of the control arm, the prospective definition of patient's subgroups and the statistical methodology were taking into account. The objective of this review was to analyze if, at this point in time, there is sufficient evidence to support the routine use of taxanes in the adjuvant setting of breast cancer, and if it is valid for all subgroups including hormone-receptor and Her2/neu positive breast cancer patients. Other objectives of this review were to define the optimal regimen for administration of taxanes, how the tolerability of taxanes may be improved and also, to investigate any potential differences in efficacy or tolerability between docetaxel and paclitaxel.

Summary Background We aimed to compare the additional benefit of gemcitabine when combined with vinorelbine above that of standard vinorelbine treatment in patients with metastatic breast cancer. Methods In this phase III, multicentre, open-label, randomised study, 252 women with locally recurrent and metastatic breast cancer who had been pretreated with anthracyclines and taxanes were randomly assigned single-agent vinorelbine (30 mg/m 2 , days 1 and 8) or gemcitabine plus vinorelbine (1200/30 mg/m 2 , days 1 and 8). Both study treatments were administered intravenously every 21 days until disease progression, unacceptable toxic effects, or stoppage at the request of investigator or patient. The primary endpoint was median progression-free survival. Secondary objectives included assessments of response rate, disease duration, overall survival, and characterisation of the toxicity profiles of both regimens. This study is registered with ClinicalTrials.gov, number NCT00128310. Findings Between 2001 and 2005, 252 women were recruited and randomised for treatment. One of these patients was ineligible. Prognostic factors were well balanced between treatment groups (median number of metastatic sites in combination group 2 (range 0–5) and in vinorelbine group 2 (range 1–6); visceral disease in 76% and 75% of patients, respectively). Median progression-free survival was 6·0 months (95% CI 4·8–7·1) for patients given gemcitabine plus vinorelbine and 4·0 months (2·9–5·1) for those assigned vinorelbine; there was 1·9 months of difference (hazard ratio 0·66 [0·50–0·88]; p=0·0028). Overall survival was 15·9 months (12·6–19·1) for the gemcitabine plus vinorelbine group and 16·4 months (11·6–21·0) for the vinorelbine group; there was 0·5 months of difference (hazard ratio 1·04 [0·78–1·39]; p=0·8046). Objective response rates were 36% for patients assigned gemcitabine plus vinorelbine (n=45) and 26% for those assigned vinorelbine (n=33) (p=0·093). Grade 3 or 4 neutropenia was reported in 75 (61% [52–70]) of the participants assigned gemcitabine plus vinorelbine, compared with 55 (44% [35–53]) of those assigned vinorelbine alone (p=0·0074). Febrile neutropenia occurred in 13 (11%) of those assigned gemcitabine plus vinorelbine, and in seven (6%) of those assigned vinorelbine alone (p=0·15). Incidences of grade 3 or 4 non-haematological toxic effects were similar between the two treatment groups. Interpretation Patients with metastatic breast cancer assigned gemcitabine and vinorelbine had better progression-free survival compared with those assigned vinorelbine alone. However, this finding did not translate into a difference in overall survival. Although toxicity was manageable, patients in the combined group had more haematological toxic effects. These factors should be taken into account when deciding which chemotherapy patients should receive.

SUMMARYThis paper describes the final development and validation of the BOMET-QoL questionnaire for assessing health-related quality of life (HRQoL) in patients with malignant bone disease due to neoplasia (MBDN).An observational prospective study was conducted of 263 patients with MBDN. Sociodemographic and clinical variables, Eastern Cooperative Oncology Group (ECOG) Performance Scale Index and Pain Management Index (PMI) were gathered. Patients completed the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and BOMET-QoL questionnaires and the perception of general health status. Both questionnaires were completed again 15 days after the baseline visit by 98 clinically stable patients (Group A), and 3 months and 6 months after the baseline visit by 165 clinically unstable patients (Group B). Prior to validation of the BOMETQoL questionnaire, a factor analysis and psychometric selection of the original items was developed by means of Rasch analysis.The BOMET-QoL questionnaire co...

The term "amyopathic dermatomyositis", or dermatomyositis "sine myositis" is used to describe those patients who present with the skin manifestations typical of dermatomyositis, but with no evidence of inflammatory myopathy. Amyopathic dermatomyositis may be associated with an underlying neoplasm, the same as with classic dermatomyositis. We present the case of a 59-year-old female patient, with cutaneous findings typical of dermatomyositis, with no proximal muscle weakness and with normal serum muscle enzymes, which stayed in a normal range throughout the later follow-up period, although the electromyogram performed six months later showed alterations with a myopathic pattern. These skin symptoms raised the suspicion of an occult neoplasm, and a recurrence of the patient's breast cancer, apparently inactive for many years, was finally found. The association of amyopathic dermatomyositis with a recurrence of breast cancer is exceptional.

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.

PURPOSE This study was undertaken to assess the antitumor activity and tolerance of chronic oral etoposide (50 mg/m2/d for 21 days every 4 weeks) in metastatic breast cancer (MBC). PATIENTS AND METHODS Forty-three consecutive metastatic breast cancer patients with at least one site of measurable disease entered the study. All patients had received prior chemotherapy (adjuvant, three patients; adjuvant plus chemotherapy for metastases, 21; chemotherapy for metastases, 19). Twenty-two and 21 patients had also received prior hormonal and radiation therapy, respectively. RESULTS Thirty-five percent of patients (15 of 43; 95% confidence interval, 21% to 51%) had objective responses, according to an intention-to-treat analysis. Responses were seen in lymph nodes (six of 14), skin and soft tissues (eight of 16), lung (six of 14), lytic lesions of the bone (two of six), liver (four of 23), and peritoneum (one of one). The median duration of response was 7 months (range, 3+ to 12). The main toxic side effects were leukopenia (overall, 65% of patients; World Health Organization [WHO] grade 4, 21%), thrombocytopenia (21%; WHO grade 4, 5%) and anemia (51%; WHO grade 4, 5%). Nine patients (21%) required a 25% dose reduction because of myelosuppression, and one patient abandoned treatment because of gastrointestinal toxicity and severe asthenia. Ninety-one percent of patients developed alopecia, 39.5% had mucositis (WHO grade 3, 9.5%) and 60.5% had some degree of emesis (11.5% nausea, 46.5% transient vomiting, 2.5% intractable vomiting). No toxic deaths occurred. CONCLUSION Chronic oral etoposide appears to be an active and well-tolerated regimen in MBC patients previously exposed to chemotherapy. This schedule of etoposide administration warrants further studies, alone or in combination, in MBC.

Summary Background Vascular endothelial growth factor (VEGF) has a crucial role in angiogenesis, and is a valid target in metastatic breast cancer. Motesanib is an investigational oral inhibitor of VEGF receptors. We aimed to determine whether treatment with motesanib plus paclitaxel is better than placebo plus paclitaxel in patients with HER2-negative locally recurrent or metastatic breast cancer. Methods Between Dec 1, 2006, and July 4, 2008, patients with untreated HER2-negative metastatic breast cancer were randomly assigned (using a randomisation list created by personnel not associated with the study) in a 1:1:1 ratio to paclitaxel (90 mg/m 2 on days 1, 8, and 15 every 3 weeks) plus either masked motesanib 125 mg orally once per day (n=91), masked placebo orally once per day (n=94), or open-label bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle (n=97), after stratification according to adjuvant or neoadjuvant chemotherapy (taxane-containing regimens vs other regimens vs none), number of metastatic sites ( vs ≥3), and hormone receptor status (positive vs negative). Placebo was provided as a replica of motesanib 25 mg tablets. The primary endpoint was objective response rate (ORR) based on the population as assigned to treatment. This trial is registered with ClinicalTrials.gov, number NCT00356681. Findings ORRs for the motesanib group and the placebo group did not differ significantly (49% vs 41%; absolute difference 8% [95% CI −6 to 22]; p=0·31). The ORR in the bevacizumab group (52%) was similar to that in the motesanib group. The most common grade 3 or higher adverse events included diarrhoea (18 of 92 patients in the motesanib group, none of 89 patients in the placebo group, and four of 96 patients in the bevacizumab group), fatigue (11, eight, and six), hypertension (11, one, and seven), and peripheral sensory neuropathy (ten, seven, and 19). More patients in the motesanib group had serious adverse events than did those in the placebo or bevacizumab groups (34, 26, and 21 patients, respectively); the most common of these in the motesanib group were gastrointestinal in nature. Interpretation Data from this trial do not support the further investigation of motesanib at this dose and schedule in this population. Funding Amgen.

The biology of breast carcinoma shows a great variation, reflected by the recent classification of phenotypes based on DNA microarrays or immunohistochemistry. The aim of this study was to determine the prevalence of insulin-like growth factor-1 receptor (IGF1R) in breast carcinoma subtypes and the impact on the outcome. We studied 197 consecutive breast carcinoma patients in stage I-II treated conservatively. Phenotypes were assessed on the basis of the expressions of ER/PR, HER2, Ki67, p53, Bcl2, CK5/6 and EGFR. Moreover, IGF1R expression (alpha-subunit and beta-phosphorylated/active form) was evaluated by immunohistochemistry, IGF1R mRNA levels by quantitative RT-PCR and IGF1R mutations by direct DNA sequencing. Overall, 40% (78/197) of tumors were luminal A, 24% (48/197) luminal B, 19% (37/197) HER2-positive and 17% (34/197) basal/triple-negative. Luminal A tumors were predominantly of low grade, without necrosis, presenting in older patients as a

Synchronous bilateral breast carcinoma (SBBC) and early onset are important characteristics of hereditary cases. The lifetime risk for breast carcinoma in Cowden syndrome (CS) is estimated to be 25-50%. We reported a 44-year-old woman presenting SBBC and characteristic mucocutaneous lesions of CS, confirmed by PTEN gene mutation analysis. Bilateral modified mastectomy and axillary dissection were performed. Histopathologic examination revealed a moderate-differentiated invasive ductal carcinoma with mixed features of luminal A immunophenotype (Estrogen and/or Progesterone Receptors > 50% and/or Ki67 < 30% of positive cells). The skin lesions showed the characteristic findings of tricholemmoma. Lack of PTEN expression was observed in all specimens. Sequencing analysis confirmed the presence of PTEN splice-acceptor site mutation in intron 8 (c.1027-2A > G), a germline mutation which had not been previously reported in CS. The patient received adjuvant chemotherapy and tamoxifen for 5 years. After 5 years of follow-up, she persists recurrence-free. SBBC with early onset suggests a hereditary predisposition. Thus, analysis of PTEN expression abnormality, easily assessed by immunohistochemistry, may be of clinical value to screen those patients with CS.

To evaluate the sequential administration of doxorubicin (A) and cyclophosphamide (C) followed by weekly docetaxel in women with stage II to IIIA breast cancer.Patients received 60 mg/m(2) of A and 600 mg/m(2) of C every three weeks for four cycles followed by 12 infusions of weekly docetaxel at a dose of 36 mg/m(2) and with a 2-week resting period.Sixty-three women were included. On an intention-to- treat basis, clinical response rate was 90% (95% CI: 83-98), with 46% complete responses. Breast-conserving surgery could be performed in 43 patients (68%). Complete pathological responses in the breast were confirmed in 17% of patients. No correlations between levels of expression of topoisomerase II alpha, survivin or p27 and the pathological response were detected. The study treatment was generally well tolerated.Neoadjuvant AC followed by weekly docetaxel is a feasible regimen for patients with early-stage breast cancer.

Combined treatments together with surgery, radiotherapy, chemotherapy, and endocrine therapy have contributed substantially to the improved survival rate in breast cancer. For more than 2 decades, tamoxifen has been the standard endocrine agent for hormone receptor-positive tumors. Third-generation aromatase inhibitors have, however, now proven to be superior to tamoxifen in the adjuvant and, more recently, the neoadjuvant treatment of postmenopausal patients. They have especially improved the surgical management of large or inoperable locally advanced breast tumors. Other advantages of neoadjuvant endocrine therapy are just emerging, but there are still many unanswered questions regarding its optimal use in this setting. A need to define how to select the patients who will benefit most from these therapies, the optimal duration of treatment, the best method to evaluate the treatment response achieved, the existence of predictive factors for response, or the superiority of certain endocrine agents over others has been observed. Other questions regarding which complementary local and systemic treatments should be administered after neoadjuvant endocrine therapy or which efficacy endpoints should be evaluated in clinical trials are also of interest. To answer as many of these questions as possible, we have carried out a critical analysis of the current literature on the use of endocrine therapy in the neoadjuvant setting of breast cancer. In this review, we outline the rationale for its use, and consider data published to date to further clarify how to optimize its administration.

Background The predictive value of IGF1R on local recurrence in invasive breast carcinoma (BC) is not well known. Methods In a series of 197 lymph-node negative BC patients treated with breast-conserving surgery and radiation therapy, we performed immunohistochemistry for alpha-IGF1R, beta-IGF1R (phosphorylated/active form) and Estrogen/Progesterone receptors. We further evaluated the IGF1R mRNA expression by quantitative RT-PCR and IGF1R mutations by direct DNA sequencing (exons 19 and 21) in 85 primary BC (42 control cases, 31 with local recurrence and 12 with distant metastasis) and in 31 local recurrences. Unconditional logistic regression analyses were performed to identify risk factors for recurrence. Results Local recurrences were associated with high-grade tumors, PR-negative and low active-IGF1R, which emerged as independent breast relapse predictors by multivariate analysis. Conclusion Patients with early BC treated with lumpectomy and radiation who have low-grade tumors and favorable markers (increased content of active IGF1R and PR-positive) have a low risk of local recurrence. Therefore, do not benefit from a boost dose on the surgical scar.

Patients with lymph node-negative breast carcinoma (LNNBC) and positive hormone receptor (HR) status during estrogen-based endocrine therapy have different prognoses. The contribution of HER-2 (human epidermal growth factor receptor-2) has not been extensively evaluated. We stained 230 LNNBCs for estrogen and progesterone receptors (ER and PR) and HER-2. HER-2 gene status was studied in 150 randomly selected tumors by chromogenic in situ hybridization and cases with discordant or nondefinitive results by fluorescence in situ hybridization. Patients with ER+ and/or PR+ tumors were treated with tamoxifen. We found positive expression of ER, PR, and HER-2 in 73.7%, 67%, and 27.8%, respectively, and HER-2 amplification in 18.0%. Poorer outcome was seen for patients with ER+ and/or PR+/HER-2 overexpressing tumors and as a trend for patients with HER-2 amplification. ER/PR and HER-2 expression showed an independent prognostic value. In LNNBCs with positive HR status, HER-2 overexpression and/or amplification confer an aggressive tumor phenotype, and this might be related to tamoxifen unresponsiveness.

The development of new anti-tumour drugs without clear cytoreductive activity has necessitated changes in the design of clinical trials. Defining the "time" parameter has become the essential objective of the majority of these trials. However, in breast cancer, this parameter is highly variable and, as such, difficult to quantify. We developed a useful tool that takes into account the inter-relatedness of all the variables known to have the capacity to predict the time-to-progression (TTP) in advanced breast cancer. From the Alamo database (GEICAM), we selected 1798 patients diagnosed as having metastatic breast cancer. Univariate analysis was performed using the method of Kaplan-Meier. Multivariate analysis was with the Cox regression method. The variables that were shown to have independent predictive value for the TTP were: non-visceral metastatic disease, single metastases, hormonal receptor positive N/T ratio2 and disease-free interval (DFI)or = 24 months. Taking into account the variables that had reached an independent predictive value, we constructed a model of scoring in which the patients were grouped according to the TTP. Using our new scoring model, it is possible to group patients with metastatic breast cancer according to the predicted TTP. This can be a useful tool at the time of selecting and stratifying patients on entry into new randomised clinical trials.

The term "amyopathic dermatomyositis", or dermatomyositis "sine myositis" is used to describe those patients who present with the skin manifestations typical of dermatomyositis, but with no evidence of inflammatory myopathy. Amyopathic dermatomyositis may be associated with an underlying neoplasm, the same as with classic dermatomyositis. We present the case of a 59-year-old female patient, with cutaneous findings typical of dermatomyositis, with no proximal muscle weakness and with normal serum muscle enzymes, which stayed in a normal range throughout the later follow-up period, although the electromyogram performed six months later showed alterations with a myopathic pattern. These skin symptoms raised the suspicion of an occult neoplasm, and a recurrence of the patient's breast cancer, apparently inactive for many years, was finally found. The association of amyopathic dermatomyositis with a recurrence of breast cancer is exceptional.

Purpose This randomized, multicenter, phase III trial evaluated whether sequential doxorubicin and docetaxel (A→T) reduced hematological toxicity, especially febrile neutropenia, compared with concomitant (AT) administration as first-line chemotherapy in metastatic breast cancer (MBC). Patients and Methods One hundred forty-four patients were randomly assigned to receive three cycles of doxorubicin 75 mg/m2 every 21 days followed by three cycles of docetaxel 100 mg/m2, every 21 days (A→T) or six cycles of the combination doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 (AT) every 21 days. Patients previously treated with anthracyclines received two cycles of doxorubicin followed by four cycles of docetaxel (A→T), or three cycles of AT followed by three cycles of docetaxel 100 mg/m2 every 21 days. Results Febrile neutropenia was less common in the A→T arm (29.3% of patients, 6.9% of cycles) compared with the AT arm (47.8% of patients, 14.8% of cycles; P = .02 and P = .0004, respectively). Asthenia, diarrhea, and fever occurred more frequently in the AT arm. The overall responses rates were 61% in the A→T arm (95% CI, 50% to 72%) and 51% in the AT arm (95% CI, 39% to 63%). The median duration of response was 8.7 months (A→T) and 7.6 months (AT); the median time to progression was 10.5 months (A→T) and 9.2 months (AT); the median overall survival was 22.3 months (A→T) and 21.8 months (AT); and no significant differences were found. Conclusion A→T significantly reduced febrile neutropenia compared with AT in MBC patients and maintains comparable antitumoral efficacy. A→T represents a valid option for the treatment of MBC.

e11079 Background: Osteopontin (OPN) plays a role in the growth, progression and metastasis of cancer. Similarly, deregulation of the signal transducer and activator of transcription (STAT)3, a mem...

Twenty-seven women with metastatic breast cancer (at least one site of measurable disease) entered a phase II study of chronic oral etoposide (50 mg/m 2 /day × 21 days, given every 4 weeks). To date, 23 patients are evaluable for response and toxicity. All patients had received prior chemotherapy (adjuvant therapy, one patient; adjuvant plus chemotherapy for metastases, six patients; chemotherapy for metastases, 16 patients). Thirteen patients had previously received anthracyclines, and 10 had also received prior hormonal therapy. Of the 23 evaluable patients, one obtained a complete response and six achieved partial responses (objective response rate 30.4%, 95% confidence interval, 13 to 53%). Responses were seen in lymph nodes (three of eight sites), skin and soft tissue (five of seven), lung (two of six), lytic lesions of the bone (one of three), and liver (1 of 12). The median duration of responses was 6 months (range, 1 + to 8). The main toxic side-effects were leukopenia (74% of patients), thrombocytopenia (22%), and anemia (69.5%). Myelosuppression in four patients (17%) necessitated a 25% dose reduction. Other toxicities included alopecia (83%), mucositis (52%), and emesis (35%). Chronic oral etoposide appears to be an active regimen in metastatic breast cancer patients previously exposed to chemotherapy.

618 Background: Notch and Jak/STAT pathways have a role in normal cell growth and development, but activation has been reported in several neoplasms. A relationship with positive hormonal receptor ...

PURPOSE The study was undertaken to assess the antitumor activity of carboplatin 400 mg/m2 intravenously every 4 weeks in metastatic breast cancer (MBC). PATIENTS AND METHODS Thirty-four MBC patients without any prior exposure to chemotherapy entered the study. All patients had measurable disease in at least one site and were assessable for response and toxicity. RESULTS Of 34 assessable patients, 12 obtained a complete (one) or partial (11) response to carboplatin, resulting in an overall response rate of 35% (95% confidence interval, 19.8% to 53.5%). The median duration of response was 8 months (range, 2+ to 12 months). Responses were seen in lymph nodes (four of six), lung (five of nine), skin and soft tissues (four of nine), breast (two of eight), and liver (three of 11), but not in measurable lytic lesions of the bone. Toxicity was mild, mainly consisting of emesis (81% of the patients; 66% of the courses), leukopenia of World Health Organization (WHO) grade 1 to 2 (47% of the patients; 18% of the courses), and thrombocytopenia (12% of the patients; 3% of the courses). There were no cases of life-threatening toxicity, although one patient developed grade 4 thrombocytopenia without bleeding. Of 22 patients who did not respond to carboplatin, 18 received salvage therapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF; 15 patients); cyclophosphamide, methotrexate, and fluorouracil (CMF; one patient); or hormones (two patients). Objective responses to CAF and hormonal therapy were seen in 11 of 15 and two of two patients, respectively. The remaining patient did not respond to CMF salvage chemotherapy. Overall, the response rate to either first-line carboplatin or second-line salvage therapy was 73.5% (25 of 34 patients). After a median follow-up time of 22 months, the median survival was 19 months. CONCLUSIONS Carboplatin is an active drug in MBC patients without previous exposure to chemotherapy. In our study, the use of an experimental drug as first-line single-agent treatment in MBC did not have a negative influence on patient survival, as the majority of the carboplatin nonresponding patients could be salvaged with a conventional therapeutic regimen.

Background: We assessed, in a double-blinded placebo-controlled trial, the effect of adding motesanib (M), a small molecule antagonist of VEGF, PDGF and Kit receptors, to paclitaxel (P) as first line treatment of subjects with MBC. A P plus bevacizumab (B) open-label arm was included. The study was supported by Amgen Inc.Methods: 282 subjects with HER2-negative and measurable MBC were randomly assigned treatment with P 90mg/m2 on days 1, 8 and 15 in combination with blinded placebo (Arm A), blinded M 125mg once daily (Arm B) or open-label B 10mg/kg on days 1 and 15 (Arm C). Treatment was administered in 28-day cycles until disease progression, toxicity or consent withdrawal. The primary objective was to compare objective response rate (ORR: CR or PR) between Arm A and B. Treatment efficacy was assessed every 8 weeks according to RECIST version 1.0 and scans were centrally reviewed.Results: 277 subjects received study treatment. Subject characteristics at entry were balanced: median age was 55, 80% had hormone receptor positive tumors and 66% had received adjuvant chemotherapy. At this analysis, 10 months after last enrolled subject, 235 subjects had completed treatment (median duration: 6 cycles). The median cumulative dose of P was similar across the arms: 1530, 1455 and 1652 mg/m2 in Arms A, B and C, respectively. Subjects received a median cumulative dose of 179 mg/kg of B (Arm C) and a median daily dose of 111 mg of M (Arm B). The table displays the efficacy results and relevant differences in toxicity incidences:More adverse events were reported in Arm B compared to the other arms, mainly grade 3 and 4 gastrointestinal toxicities, hepatobiliary toxicities and hypertension. Infections and stomatitis were more frequently reported in Arm C. Venous thrombo-embolic events were similar across all three arms. Among serious hepatobiliary disorders, 5 subjects experienced serious cholecystitis or gallbladder enlargement: 4 of them were managed by surgery and 4 subjects could resume study treatment.The ORR favored Arms B and C as compared to Arm A, with 49%, 52% and 41% respectively but the difference between Arm A and B was not statistically significant (p=.31, adjusting for stratification factors). Stable disease lasting at least 24 weeks was reported for 34%, 36% and 33% of subject in Arms A, B and C respectively. The Progression-Free Survival (PFS) did not significantly differ between the three arms.Conclusion: The antitumor effect of P and M is comparable to P and B as treatment of subjects with HER2-negative MBC but P and M increases toxicities compared to the other arms. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 47.

604 Background: Node-positive BC pts treated with TAC have a longer disease-free and overall survival but a higher rate of febrile neutropenia (FN) compared with pts treated with FAC. We evaluated ...