HER2-negative Advanced Breast Cancer Patients Research Articles

Cisplatin monotherapy as a treatment option for patients with HER-2–negative breast cancer facing hepatic visceral crisis or impending visceral crisis: A single-center cohort study.

e13057 Background: The international consensus guidelines, ESO-ESMO's fifth edition, characterize visceral crisis (VC) in advanced breast cancer (ABC) as a swift rise in bilirubin during disease progression. The guidelines also briefly address the impending VC (IVC) definition. Systemic treatment data for hepatic VC/IVC are scarce and lacking in international guidelines regarding BC treatment. This study explores cisplatin monotherapy's safety and efficacy in HER2-negative BC patients with hepatic IVC/VC. Methods: In this retrospective cohort study conducted at a Reference Cancer Center in Southern Poland, data from HER2 negative ABC patients who underwent cisplatin monotherapy (60-80mg/m2, every 3-4 weeks) between 2016 and 2023 were examined. Hepatic VC followed ABC5 definition of rapid bilirubin elevation >1.5 times the upper limit of normal (ULN) due to diffuse liver metastases, in the absence of biliary tract obstruction or Gilbert's syndrome; IVC was characterized by rapid, symptomatic liver progression, a majority of liver involvement, with ALT or AST >2 x ULN, and significant increases in LDH, alkaline phosphatase, or GGTP. Results: The study included 33 female participants (24 hormonal positive) with a mean age of 53.8 years (range 34-77). Among them, 10 were identified with hepatic VC, and 23 with IVC. Median number of previous palliative systemic treatment lines was 2 (range: 0-5). The median progression-free survival was 1.87 months and the median overall survival was 2.67 months. Patients received median 1 cycle of cisplatin (1-6): 17 patients received only one cycle, 6 patients two cycles and 10 patients ≥three cycles. Using the Conditional Inference Trees algorithm allowed to assess that patients with performance status (PS) 0 or 1 (15 patients) had a 66.67% chance of achieving stable disease (SD) or partial regression (PR) as the best response, while patients with PS ≥2 (18 patients) had a 5.6% chance of achieving SD or PR as per Response Evaluation in Solid Tumors 1.1 Criteria (median time from cisplatin initiation to imaging studies 2.23 months). Eight patients experienced adverse events of grade ≥3, such as fatigue or nephrotoxicity leading to dose reduction in 5 cases and treatment discontinuation in 2. Conclusions: The differentiation between IVC and VC lacks precision. Due to the hepatotoxicity of BC-active drugs, specific recommendations for systemic treatment are lacking. Our study explored cisplatin's potential use, finding it to be a feasible choice in patients with PS ≤1 experiencing hepatic IVC/VC, regardless of liver function parameters. Almost one-third of our patients were administered treatment in the last 30 days of life, potentially adversely affecting their quality of life and causing unwarranted suffering and costs. Academic clinical trials should be organized to address this pressing medical gap.

Abstract PO2-05-06: Palbociclib in advanced hormone receptor positive breast cancer: A real world study in South America

Abstract BACKGROUND: First-line combined endocrine therapy is the standard of care for hormone receptor-positive (HR+) human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC). Palbociclib, in combination with aromatase inhibitors or fulvestrant, is a treatment option for HR+/HER2-negative ABC patients. We aimed to analyze the real-world experience of palbociclib in this setting in South America. METHODS: Real-world study collecting sociodemographic and clinical data from women with ABC treated with palbociclib in centers from Chile (n = 40), Perú (n = 61), and Ecuador (n = 10). Treatment efficacy and safety were analyzed. RESULTS: The median age was 54 years (range: 28 – 83), and 81.1% of women had received previous treatment: adjuvant therapy (20.0%), ABC treatment (31.1%), or both (48.9%). The median duration of palbociclib treatment was 14 months (range: 1 – 57), with differences among countries (longer in Perú; p = 0.009). The dose was reduced in 28.2% of women and only 6.5% returned to the previous one. Most women (97.3%) received combined endocrine therapy, letrozole (48.1%) or fulvestrant (44.4%), with differences between countries (p < 0.001). Palbociclib was usually the first-line therapy in Ecuador (60.0%) and Perú (80.3%), and the third line in Chile (37.5%). Considering all women, it was the first- or second-line therapy for 52.3% and 20.7% of them, respectively. The overall response rate was 34.2% and progressive disease was significantly lower in patients receiving first-line palbociclib (25.9 vs. 66.0%, p < 0.001). The disease-free survival was longer than 12 months in 67.2% of patients treated with first-line palbociclib. Regarding safety, 38.7% of women had any relevant adverse event (AE) during the treatment, most frequently neutropenia (39.5%), diarrhea (9.3%), and elevated transaminase levels (4.7%). The number of patients who developed any relevant AE was lower among the first-line treated patients (19.0% vs. 60.4%, p< 0.001). CONCLUSION: The study reflects differences among countries in routine palbociclib use. But considering all data, palbociclib has confirmed its efficacy and safety, supporting its use in HR+/HER2-negative patients, especially as a first-line therapy. Citation Format: Cesar SÁNCHEZ, Suraj Samtani, Henry Gómez, Silvia Falcon-Lizaraso, René Muñoz, Tannia Soria. Palbociclib in advanced hormone receptor positive breast cancer: A real world study in South America [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-05-06.

Abstract PO5-16-12: EFFICACY AND TOLERABILITY OF METRONOMIC CHEMOTHERAPY (mChT) WITH CYCLOPHOSPHAMIDE, METHOTREXATE AND CAPECITABINE (CMX) IN PATIENTS WITH HEAVILY PRETREATED ADVANCED BREAST CANCER. RESULTS FROM A MULTICENTER RETROSPECTIVE STUDY

Abstract BACKGROUND mChT consists on the administration of repetitive, low doses of chemotherapy drugs and represents an attractive and active therapeutic strategy in cancer patients. Beyond the traditional cytotoxic effect of each drug on tumor cells, mChT seems to play a role in the modulation of angiogenesis and immune-regulation. mChT has demonstrated promising clinical activity and low toxicity in patients with advanced breast cancer (ABC). The aim of this study is to describe the safety and efficacy of CMX in a retrospective cohort of heavily pretreated HER2-negative ABC patients. METHODS This is a multicenter, retrospective study that included patients with HER2-negative ABC who received treatment with CMX (capecitabine 500 mg thrice daily, methotrexate 2.5 mg twice a week, and cyclophosphamide 50 mg daily). Demographic data, tumor characteristics, previous therapies, efficacy, and toxicity of the CMX treatment were collected. Statistical analyses were performed with Stata v.14. For standard summary statistics, mean and range for continuous data and relative and absolute frequencies for categorical data were used while for survival analysis Kaplan Meier approach was employed. RESULTS A total of 25 patients from 4 centers in Spain treated between October 2016 and February 2023 were included in this analysis. Median age was 63 years (range: 37-87), 68% had visceral disease, and 48% had triple-negative tumors. All patients previously received a median of 5 prior lines of systemic therapy in the metastatic setting and 80% of patients had been treated with capecitabine, most of them in the metastatic scenario with a median treatment duration of 6.2 months. Dose reductions were necessary in 5 patients and 1 patient discontinued treatment due to toxicity. No grade 3-4 hand-foot syndrome or diarrhea were reported. Objective response rate was 20.8% and disease control rate was 54.2%. Median progression-free survival was 6.1 months (95% confidence interval [CI] 95%; 4.3 - 12.4) and median overall survival was 12.3 months (95% CI; 6.8 - 24.7). Neither the number of previous lines of treatment nor the prior use of capecitabine showed a negative impact on the efficacy of CMX. CONCLUSIONS CMX is an effective and well-tolerated scheme of mChT and may represent an adequate treatment option for patients with heavily pretreated HER2-negative ABC, including those patients that previously received capecitabine as single agent. These encouraging data warrant further investigation. Citation Format: Cristina Saavedra, María Gion, Alfonso Cortés, Patricia Cortez, Laia Garrigós, José Manuel Pérez-García, Gabriele Antonarelli, Javier Cortés. EFFICACY AND TOLERABILITY OF METRONOMIC CHEMOTHERAPY (mChT) WITH CYCLOPHOSPHAMIDE, METHOTREXATE AND CAPECITABINE (CMX) IN PATIENTS WITH HEAVILY PRETREATED ADVANCED BREAST CANCER. RESULTS FROM A MULTICENTER RETROSPECTIVE STUDY [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-16-12.

A Real-world Study of Everolimus Plus Aromatase Inhibitor in Hormone Receptor-positive, HER2-negative Advanced Breast Cancer.

Everolimus in combination with exemestane was shown to offer benefit versus exemestane monotherapy in hormone receptor (HR)-positive, HER2-negative advanced breast cancer patients who progressed after aromatase inhibitor (AI) therapy. The medical records of metastatic breast cancer patients, treated with everolimus, were retrospectively reviewed to generate real life safety and efficacy data. Sixty-eight percent of the patients had received chemotherapy (for early or metastatic disease) and 26% had received chemotherapy for metastatic disease. Among the 25 included patients, the most common adverse events were fatigue, neutropenia, epistaxis, stomatitis, and pneumonitis. Toxicity led to treatment discontinuation in 3 patients (12%). The median progression-free survival (PFS) was 7 months (95%CI=3.5-10.5). With a median follow-up of 73.3 months, the median overall survival was not reached. Twenty-five percent of the patients had received prior therapy with CDK4/6 inhibitors. Median PFS was significantly shorter in this subgroup (p=0.025). There was also a trend towards a longer PFS in patients with grade 3 breast cancer (p=0.085) and in patients receiving everolimus as first-line treatment (p=0.081). Some long responses were noted, with four patients exhibiting a PFS >5 years. These real-life data show that everolimus in combination with AI in patients with HER2-negative, HR-positive advanced breast cancer is an effective treatment with an acceptable toxicity profile.

Abstract HER2-02: HER2-02 HER2-Low Status is Associated with Worse Clinical Outcomes in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer Patients Treated With First-Line Cyclin-Dependent Kinase 4/6 Inhibitors Plus Endocrine Therapy

Abstract Introduction: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) are the standard first-line treatment for patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (HR+/HER2- aBC). HER2-low BC, which is defined by an IHC score for HER2 of 1+ or 2+ with negative ISH assay, accounts for more than half of all HR+/HER2- aBC cases, and it is associated with remarkable clinical benefit from the novel anti-HER2 antibody drug conjugate (ADC) trastuzumab-deruxtecan. Evidence on the prognostic impact of HER2-low status is controversial in both limited-stage and advanced BC. Here, we sought to investigate the possible prognostic relevance of HER2-low status in a population of aBC patients treated with CDK4/6i plus ET. Methods: We conducted a retrospective-prospective study in six Italian Cancer Centers to investigate the impact of HER2 status (low vs. 0) on the progression-free survival (PFS) and overall survival (OS) of consecutive HR+/HER2- aBC patients treated with CDK4/6i plus ET (aromatase inhibitors or fulvestrant) as a first-line therapy. In the main study analysis, we considered HER2 status in the last tumor assessment (i.e., primary tumor, or, when available, a metastatic lesion). We also performed a subgroup analysis including only patients with HER2 status evaluation in a metastatic lesion collected before CDK4/6i plus ET therapy initiation. The association between HER2 status (low vs. 0) and PFS or OS was evaluated using log-rank test and Cox regression modeling. Results: We evaluated 767 consecutive HR+/HER2- aBC patients treated with CDK4/6i plus ET between January 2017 and January 2022. Of these, 436 patients (56.8%) received CDK4/6i plus ET as a first-line therapy, and they were included in this analysis. Median age was 63 years (range 27-87), and 362 patients (83.0%) were postmenopausal. The majority of patients were treated with palbociclib (68.3%), while 91 (20.9%) and 47 (10.8%) patients received ribociclib and abemaciclib, respectively. Regarding HER2 status, 269 (62.9%) patients had HER2-low tumors, while 159 (37.1%) patients had HER2-0 neoplasms. HER2-low status was associated with significantly lower PFS when compared to HER2-0 status [median PFS (mPFS) 23.6 vs. 32.3 months, respectively; p=0.014]. HER2-low status was also associated with significantly worse OS (mOS 48.7 vs 58.3 months, respectively; p=0.025). These results were confirmed in multivariable models adjusting the impact of HER2 status for clinically-relevant covariates, namely estrogen receptor status, Ki-67, age, number of metastatic sites, presence of liver metastases, disease free interval, ECOG Performance Status. In this analysis, HER2-low status, compared with HER2-0 status, was independently associated with worse PFS [adjusted Hazard Ratio (aHR): 1.62; 95% confidence interval (CI): 1.17-2.24; p< 0.01] and OS (aHR: 1.74; 95% CI: 1.09-2.76; p=0.019). Subgroup analysis conducted in the subset of 256 patients with available metastatic tumor samples collected before CDK4/6i plus ET initiation confirmed that HER2-low status (n=157), when compared to HER2-0 status (n=99), was independently associated with worse PFS (mPFS 24.5 vs 35.2 months, p=0.01; aHR 2.07; 95% CI: 1.28-3.34, p< 0.01) and worse OS (mPFS 48.7 vs 72.3 months, p=0.027; aHR 3.12; 95% CI 1.44-6.77, p< 0.01). Conclusions: This multicenter Italian study revealed that HER2-low status has independent, negative prognostic value in patients with HR+/HER2- aBC treated with CDK4/6i plus ET in the first-line setting. Our results suggest that HER2-low status might be associated with different clinical benefit from standard anticancer therapies in specific clinical settings. The definition of treatment algorithms also taking into account HER2 status is a clinical priority in patients with HR+/HER2- aBC. Citation Format: Emma Zattarin, Caterina Sposetti, Rita Leporati, Luigi Mariani, Alice Menichetti, Chiara Corti, Chiara Benvenuti, Giovanni Fucà, Riccardo Lobefaro, Francesca Ligorio, Daniele Presti, Leonardo Provenzano, Andrea Vingiani, Gaia Griguolo, Marianna Sirico, Ottavia Bernocchi, Antonio Marra, Paola Zagami, Elisa Agostinetto, Flavia Jacobs, Pierluigi Di Mauro, Andrea Esposito, Carlo Alberto Giorgi, Luca Lalli, Laura Boldrini, Pier Paolo Maria Berton Giachetti, Ambra Carnevale Schianca, Valentina Guarneri, Rebecca Pedersini, Agnese Losurdo, Alberto Zambelli, Daniele Giulio Generali, Giuseppe Curigliano, Giancarlo Pruneri, Filippo de Braud, Maria Vittoria Dieci, Claudio Vernieri. HER2-02 HER2-Low Status is Associated with Worse Clinical Outcomes in Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer Patients Treated With First-Line Cyclin-Dependent Kinase 4/6 Inhibitors Plus Endocrine Therapy [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 HER2-02.

Peripheral blood lymphocytes predict clinical outcomes in hormone receptor-positive HER2-negative advanced breast cancer patients treated with CDK4/6 inhibitors.

Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) combined with Endocrine Therapy (ET) are the standard treatment for patients with Hormone Receptor-positive/HER2-negative advanced breast cancer (HR+/HER2- aBC). While CDK4/6i are known to reduce several peripheral blood cells, such as neutrophils, lymphocytes and platelets, the impact of these modulations on clinical outcomes is unknown. A multicenter, retrospective-prospective Italian study. We investigated the association between baseline peripheral blood cells, or their early modifications (i.e. 2 weeks after treatment initiation), and the progression-free survival (PFS) of HR+/HER2- aBC patients treated with ETs plus CDK4/6i. Random Forest models were used to select covariates associated with patient PFS among a large list of patient- and tumor-related variables. We evaluated 638 HR+/HER2- aBC patients treated with ET plus CDK4/6i at six Italian Institutions between January 2017 and May 2021. High baseline lymphocyte counts were independently associated with longer PFS [median PFS (mPFS) 20.1 versus 13.2 months in high versus low lymphocyte patients, respectively; adjusted Hazard Ratio (aHR): 0.78; 95% confidence interval (CI): 0.66-0.92; p = 0.0144]. Moreover, patients experiencing a lower early reduction of lymphocyte counts had significantly longer PFS when compared to patients undergoing higher lymphocyte decrease (mPFS 18.1 versus 14.5 months; aHR: 0.82; 95% CI: 0.73-0.93; p = 0.0037). Patients with high baseline lymphocytes and undergoing a lower reduction, or even an increase, of lymphocyte counts during CDK4/6i therapy experienced the longest PFS, while patients with lower baseline lymphocytes and undergoing a higher decrease of lymphocytes had the lowest PFS (mPFS 21.4 versus 11 months, respectively). Baseline and on-treatment modifications of peripheral blood lymphocytes have independent prognostic value in HR+/HER2- aBC patients. This study supports the implementation of clinical strategies to boost antitumor immunity in patients with HR+/HER2- aBC treated with ETs plus CDK4/6i.

Absolute Lymphocyte Count Is an Independent Prognostic Factor for ER-positive HER2-negative Advanced Breast Cancer Patients Treated With CDK4/6 Inhibitors.

The aim of this study was to elucidate the clinical significance of peripheral blood biomarkers, including absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and C-reactive protein (CRP) in patients with estrogen receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer treated with the CDK4/6 inhibitors, abemaciclib and palbociclib. A total of 83 patients treated with fulvestrant plus abemaciclib or palbociclib were included in this study. Progression-free survival (PFS) and overall survival (OS) were compared in relation to baseline levels of ALC, NLR, PLR and CRP. The cut-off values of ALC, NLR, PLR, and CRP for PFS were determined from the receiver operating characteristic curve using the Youden index for area under the curve and set at 1,212/μl, 1.964, 170 and 0.220 mg/dl, respectively. In the abemaciclib-treated group, ALC-high patients showed significantly better PFS than ALC-low patients (p=0.0151) and multivariate analysis revealed that ALC was an independent prognostic factor for PFS (p=0.0085). In the palbociclib-treated group, there was no significant relationship between any peripheral blood biomarkers and PFS. In both treatment groups, ALC-high patients showed significantly better OS than ALC-low patients (p=0.0169 and 0.0290, respectively). Multivariate analysis revealed ALC was an independent prognostic factor for OS in both abemaciclib- and palbociclib-treated groups (p=0.0112 and 0.0202, respectively). ALC is an independent prognostic factor for estrogen receptor-positive human epidermal growth factor receptor 2-negative advanced breast cancer patients treated with the CDK4/6 inhibitors abemaciclib and palbociclib.

Prophylactic use of metformin in patients on alpelisib treatment.

e13040 Background: Alpelisib-induced hyperglycemia (HG) is the most common adverse event leading to interruption, reduction or withdrawal of the treatment. HG is an on-target effect that depends on the baseline metabolic status of the patient. In SOLAR-1 90,6% patients with high-risk at baseline HG G3/G4 was reported. Prophylactic use of metformin may prevent HG in patients at risk. Methods: HR+ HER2-negative advanced breast cancer patients were stratified to low-, moderate- or high-risk groups of HG based on the algorithm published in [1] before starting alpelisib 300 mg + fulvestrant (Alp + Fulv). Moderate- and high-risk patients used prophylactic metformin at 500-1000 mg or 2000 mg BID with breakfast and dinner (Table). Metformin was started at least one-week prior Alp administration. Fasting plasma glucose (FPG) was monitored qw and bw in low- and moderate-risk patients, and daily with home glucometer in addition to bw FPG for high-risk patients. The primary endpoint of retrospective analysis was to assess the incidence of HG G3/G4 in different risk groups based on CTCAE V4.03 guidelines. Results: A cohort of 18 patients (median lines of previous treatment in advanced disease was five, all patients has received CDK4/6 inhibitors) treated with Alp+Fulv in the Loginov Moscow Clinical Scientific Centerin 2020-2021 included 7 low-, 3 moderate- and 8 high-risk patients. Any grade HG was reported in 13 out of 18 pts; no cases of HG G2 or G4 were detected. HG G3 was reported in 5 out of 18 patients including in 2 out of 3 moderate-risk patients, and in 3 out of 8 high-risk patients. Anti-HG drugs used included metformin (6/18); empagliflozin (4/18), and linagliptin (1/18); 1 patient required Alp dose reduction to 250 mg due to HG G3; none discontinued Alp due to AEs. Other AEs included rash (7/18; no grade 4; grade 3 in 4/18), and blood creatinine increase (8/18 – all grade 1-2).The median PFS on treatment with Alp+Fulv was 7 months. Conclusions: Prophylactic use of metformin in patients with high risk of hyperglycemia could markedly reduce frequency and severity of hyperglycemia on alpelisib.[Table: see text]

Abstract P1-17-08: Abemaciclib and endocrine therapy for hormone receptor-positive, HER2-negative advanced breast cancer: A real-world UK multicentre experience

Abstract Background Abemaciclib is approved in 1st and 2nd line for hormone receptor (HR)-positive HER2-negative advanced breast cancer (ABC). However, outcomes on this agent are unclear in the real world.We determined the safety and efficacy profile of abemaciclib across 15 institutions in the United Kingdom. Methods We retrospectively identified HR-positive, HER2-negative ABC patients who received abemaciclib between July 2018 and June 2020. Demographics, disease characteristics, prior treatments, blood tests, toxicities, treatment delays and responses were recorded. Simple statistics, Fisher’s exact test, chi-squared method and Cox regression were used as appropriate. Results 228 patients identified had median age of 64 (31-93). 172 (75.4%) were postmenopausal and 209 (91.7%) had ECOG Performance Status 0-1. 145 (63.6%) had visceral involvement and 44 (19.3%) only bone disease. Patients received a median 1 (range 0-7) prior lines of treatment and 0 (range 0-5) prior chemotherapy lines.148 patients (64.9%) experienced diarrhoea (grade ≥3 in 16 [7.0%]). 146 patients (64.0%) developed neutropenia (grade ≥3 in 40 [17.5%]). 5 experienced febrile neutropenia (2.2%). 32 patients (14.0%) required hospitalisation due to toxicity (diarrhoea in 9 [3.95%]).Dose reductions were required in 107 patients (46.9%), mainly due to diarrhoea (55 [24.1%]) and to 50mg BD in 30 patients (13.2%). Dose delays were in median 14 (range 2-118). Abemaciclib was discontinued in 121 patients (53.1%) due to disease progression in 61 (26.7%) and toxicity in 48 (21.0%) (diarrhoea in 16 [7.0%]).Abemaciclib produced clinical benefit rate of 82.8% and overall response rate of 47.2% in 163 patients assessed. Overall, median progression-free survival (PFS) was 6.4 months (95% confidence interval [CI] 4.4-7.8) and median overall survival (OS) was 8.8 months (95% CI 7.6-10.6). Conclusions This a large real-world analysis of the safety and efficacy of abemaciclib in combination with endocrine therapy for advanced HR-positive breast cancer. In this analysis, the rates of diarrhoea were lower compared with the pivotal trial data, while neutropenia was more frequent. Although the PFS outcomes were similar to those previously reported, median OS was worse in this cohort which may reflect the different population of patients included, who were older and had more frequent visceral involvement. The selection of patients suitable for abemaciclib is crucial to ensure adequate efficacy and safety outcomes in this setting. Citation Format: Nicolò Matteo Luca Battisti, Laura Morrison, Tamsin Nash, Nishanti Senthivel, Samantha Kestenbaum, Parvin Begum, Mariam Obeid, William Hayhurst, Dorothy Yang, Shafiah Gafoor, Caroline Brown, Farah Rehman, Laura Kenny, Olivia Hatcher, Susan Susan, Jennet Williams, Anna Brown, Hamoun Rozati, Alexandros Alexandros, Elinor Sawyer, Charalampos Gousis, Eleni Karapanagiotou, Anna Rigg, Kleopatra Rapti, Rebecca Roylance, Mark Beresford, Abigail L Gee, Apostolos Konstantis, Judy King, Mark Nathan, Emma Spurrell, Mark Pearce, Dane Bradwell, Arshi Denton, Kate Swain, Sophie McGrath, Mark Allen, Alistair Ring, Stephen Johnston, Fharat Raja. Abemaciclib and endocrine therapy for hormone receptor-positive, HER2-negative advanced breast cancer: A real-world UK multicentre experience [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 P1-17-08.

POSB120 Economic Assessment of Ribociclib for the Treatment of Postmenopausal Patients with Advanced Breast Cancer HR-Positive, HER2-Negative.

To estimate the cost-effectiveness of ribociclib (Kisqali ®) + letrozole versus palbociclib + letrozole in the treatment of HR-positive, HER2-negative advanced breast cancer patients in the first line of treatment from the perspective of the National Cancer Institute of Panama (ION).

TAKTIC: A prospective, multicentre, uncontrolled, phase IB/II study of LY2780301, a p70S6K/AKT inhibitor, in combination with weekly paclitaxel in HER2-negative advanced breast cancer patients

BackgroundHormone-resistant HER2-negative or triple-negative advanced breast cancers (ABC) are routinely treated with paclitaxel chemotherapy. LY2780301 is a dual inhibitor of p70 ribosomal protein S6 kinase and AKT. The TAKTIC study aimed at exploring the combination of paclitaxel and LY2780301 in this population. MethodsIn this multicentric phase Ib/II trial, we enrolled patients with HER2-negative ABC, with (phase IB) or without (phase II) prior to cytotoxic treatment for advanced disease. Oral LY2780301 was administered once daily in combination with intravenous weekly paclitaxel. Primary endpoints were to determine the recommended phase II dose (RP2D) of the combination of LY2780301 with weekly paclitaxel (phase Ib), and to estimate a 6 months objective response rate (ORR) (phase II) in patients with HER2-negative ABC, both in the overall patient population and in cases with activation of the PI3K/AKT pathway (PI3KAKT+). ResultsA total of 51 patients were enrolled; RP2D was LY2780301 500 mg QD+ paclitaxel 80 mg/m2. Main drug-related adverse events noted in phase Ib included neuropathy (75% of patients, grade 3–4 in 8%), asthenia (58% of patients, no grade 3–4), and ungual toxicity (50% of patients, grade 3–4 in 25%). They were similar in the phase II part, except that 14% of patients experienced pneumonia (grade 3–4 in 6%). In the phase II part, 6-month ORR in the overall population and in PI3KAKT+ subgroup were, respectively, 63.9% [48.8–76.8] and 55% [35–73.7]. ConclusionCombining LY2780301 and weekly paclitaxel in patients with HER2-negative ABC was feasible with preliminary evidence of efficacy in both the overall population and the PI3KAKT+ subgroup. Trial registration idNCT01980277.

Pembrolizumab Plus Gemcitabine in the Subset of Triple-Negative Advanced Breast Cancer Patients in the GEICAM/2015-04 (PANGEA-Breast) Study.

Simple SummaryAdvanced triple-negative breast cancer (TNBC) remains an extremely challenging situation in oncology, where new therapeutical strategies are desperately needed. Immunotherapy has opened a window of opportunity in this setting, with some promising results with chemo-immunotherapeutic schedules based on anti-PD1/PD-L1 agents, especially in the PD-L1-positive cohort. However, there is certainly room for improvement; thus, new schemes that could potentially boost synergism against cancer cells must be explored. This work analyzes the effects of combination therapy with anti-PD1 (pembrolizumab) and gemcitabine, specifically in the TNBC cohort of the PANGEA-Breast trial. Patients included in this study were not selected by PD-L1 status, and most of them were also heavily pretreated, which could explain the modest objective response rate of 15% achieved. Complementary translational subanalyses, focused on T infiltrating lymphocytes, myeloid-derived suppressor cells, and PD-L1 were accomplished.The PANGEA-Breast trial evaluated a new chemo-immunotherapeutic combination that would synergistically induce long-term clinical benefit in HER2-negative advanced breast cancer patients. Treatment consisted of 21-day cycles of 200 mg of pembrolizumab (day 1) plus gemcitabine (days 1 and 8). The primary objective was the objective response rate (ORR). The tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumor, and the myeloid-derived suppressor cells (MDSCs) level in peripheral blood, were analyzed to explore associations with treatment efficacy. Considering a two-stage Simon’s design, the study recruitment was stopped after its first stage as statistical assumptions were not met. A subset of 21 triple-negative breast cancer (TNBC) patients was enrolled. Their median age was 49 years; 15 patients had visceral involvement, and 16 had ≤3 metastatic locations. Treatment discontinuation due to progressive disease (PD) was reported in 16 patients. ORR was 15% (95% CI 3.2–37.9). Four patients were on treatment >6 months before PD. Grade ≥3 treatment-related adverse events were observed in 8 patients, where neutropenia was the most common. No association was found between TILs density, PD-L1 expression or MDSCs levels and treatment efficacy. ORR in TNBC patients also did not meet the assumptions, but 20% were on treatment >6 months.

Abstract PD10-12: Genomic analysis from the talazoparib beyond BRCA clinical trial: Homologous recombination (HR) deficiency scores, loss-of-heterozygosity and mutations in non-BRCA1/2 mutant tumors with other HR mutations

Abstract Background: Talazoparib, a PARP1 inhibitor, is active in germline BRCA1/2 mutant advanced HER2-negative breast cancer, but its activity beyond BRCA1/2 less well understood. The Talazoparib Beyond BRCA clinical trial treated 20 patients with germline (g) or somatic (s) mutations in HR pathways genes other than BRCA1/2, which included PALB2, CHEK2, ATM, BRIP1, RAD50, ATR, PTEN, and FANCA. Talazoparib treatment was associated with a 31% overall response rate in patients with breast cancer, including tumor regression from baseline as best response in 6 out of 6 patients treated gPALB2 mutations. We now present the results of additional genomic studies to further characterize treatment responses and resistance mechanisms. Methods: Primary and metastatic tumor biopsies were assessed using the commercially-available next-generation sequencing HRD assay (Myriad). Panel gene sequencing of tumors was performed for 108 genes associated with genomic instability. Loss-of-heterozygosity (LOH) was assessed in tumors. Tumor/normal exome sequencing identified pre-treatment somatic variants. Circulating-tumor DNA at baseline and disease progression was assessed by targeted panel sequencing and plasma whole exome sequencing. Results: Of the 18 HRD assays performed, 3 failed and were thus excluded. Seven patients had HRD analysis performed on both primary and metastatic tumors. For these patients the HRD score was significantly higher in the metastasis versus the primary (means 46.2 versus 36.5, p = 0.018 by paired t-test). By panel sequencing of tumors (n=18) the most common alterations detected included mutations in PIK3CA (n=8), PALB2 (n=6), ATM (n=5), KRAS (n=4), PTEN (n=5) and TP53 (n=4). In all cases except one, the HR-associated mutation used as entry criteria were detected. LOH analysis showed that of tumors with gPALB2 mutations, 3 of the 6 had LOH for PALB2, and an additional two tumors had 2 independent PALB2 mutations suggesting bi-allelic inactivation. The one remaining tumor had an uncertain LOH result due to test failure. Thus, it is likely that most, if not all, of the tumors in our cohort with gPALB2 mutations had complete inactivation of PALB2 gene function. Other detected mutations that were associated with LOH included all sTP53 mutations (n=4), all gCHEK2 mutations (n=3), gFANCA (n=1), all sRB1 mutations (n=3) and NF1 (n=1). Of the three gATM mutations one had LOH, while the others had two independent mutations, suggestive of bi-allelic inactivation. sATM mutations were associated with LOH in a breast cancer and with 2 independent (possibly bi-allelic) mutations in a non-breast cancer. Additional results from ctDNA targeted sequencing and plasma whole exome sequencing of baseline and progression samples will be presented. Conclusions: In this proof-of-concept phase II study, talazoparib demonstrated activity in HER2-negative advanced breast cancer patients with a HR pathway mutation beyond BRCA1/2, especially in patients with gPALB2 mutations and high HRD scores. These additional genomic analyses provide evidence that HRD scores may be significantly higher in metastatic samples compared to primary tumors. Also, we detected either LOH or bi-allelic inactivation for most HR-associated mutations used to determine eligibility. These findings may inform selection of patients for PARP inhibitor monotherapy beyond BRCA1/2. Citation Format: Joshua J Gruber, Anosheh Afghahi, Alyssa Hatton, Wyatt Gross, Jessica Foran, Alex McMillan, James M Ford, Melinda L Telli. Genomic analysis from the talazoparib beyond BRCA clinical trial: Homologous recombination (HR) deficiency scores, loss-of-heterozygosity and mutations in non-BRCA1/2 mutant tumors with other HR mutations [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 PD10-12.

Machine learning and natural language processing (NLP) approach to predict early progression to first-line treatment in real-world hormone receptor-positive (HR+)/HER2-negative advanced breast cancer patients.

CDK4/6 inhibitors plus endocrine therapies are the current standard of care in the first-line treatment of HR+/HER2-negative metastatic breast cancer, but there are no well-established clinical or molecular predictive factors for patient response. In the era of personalised oncology, new approaches for developing predictive models of response are needed. Data derived from the electronic health records (EHRs) of real-world patients with HR+/HER2-negative advanced breast cancer were used to develop predictive models for early and late progression to first-line treatment. Two machine learning approaches were used: a classic approach using a data set of manually extracted features from reviewed (EHR) patients, and a second approach using natural language processing (NLP) of free-text clinical notes recorded during medical visits. Of the 610 patients included, there were 473 (77.5%) progressions to first-line treatment, of which 126 (20.6%) occurred within the first 6 months. There were 152 patients (24.9%) who showed no disease progression before 28 months from the onset of first-line treatment. The best predictive model for early progression using the manually extracted dataset achieved an area under the curve (AUC) of 0.734 (95% CI 0.687-0.782). Using the NLP free-text processing approach, the best model obtained an AUC of 0.758 (95% CI 0.714-0.800). The best model to predict long responders using manually extracted data obtained an AUC of 0.669 (95% CI 0.608-0.730). With NLP free-text processing, the best model attained an AUC of 0.752 (95% CI 0.705-0.799). Using machine learning methods, we developed predictive models for early and late progression to first-line treatment of HR+/HER2-negative metastatic breast cancer, also finding that NLP-based machine learning models are slightly better than predictive models based on manually obtained data.

Olaparib for advanced breast cancer.

Olaparib, an oral PARP-inhibitor, has shown clinical benefit for HER2-negative advanced breast cancer patients carrying a germinal BRCA1/2 mutation. In a randomized Phase III trial, olaparib significantly prolonged progression-free survival as compared with chemotherapy of physician choice. Moreover, in the same trial, a prespecified subgroup analysis reported an overall survival benefit for patients not previously pretreated with chemotherapy for metastatic disease. This review focuses on available preclinical, pharmacokinetic and pharmacodynamic data regarding olaparib and clinical evidence of its antitumor efficacy (both as monotherapy and in combination) and tolerability in breast cancer patients. Open questions, such as use of appropriate biomarkers for patient selection and combination/sequencing with other anticancer drugs, are also addressed.

Real-world efficacy and safety of eribulin in advanced and pretreated HER2-negative breast cancer in a Spanish comprehensive cancer center

BackgroundEribulin improves survival in pre-treated HER2-negative advanced breast cancer (ABC). However, limited data exist on co-morbidities and central nervous system (CNS) efficacy. The purpose of this study was to review eribulin’s efficacy and safety in everyday clinical practice with special focus on age, body mass index (BMI) and central nervous system (CNS) activity.MethodsAn observational study was conducted in a series of HER2-negative ABC patients treated from January’14-December’17 outside a clinical trial. Objective Response Rate (ORR), Progression Free Survival (PFS), Overall Survival (OS), and association of clinical and pathological variables with outcome were evaluated.ResultsNinety-five women were treated with at least one cycle of eribulin. Median age was 57 (33–83), and 18% were obese. Median number of prior chemotherapies for ABC was 3 (2–5) and 76% of patients had visceral metastases, including 21% with CNS involvement. Most tumors were estrogen receptor-positive (79%). ORR and stable disease (SD) at 6 months were 26.2 and 37.5%, respectively. Remarkably, relevant CNS efficacy was observed with eribulin: 20% of patients obtained partial response and 25% SD. Treatment was generally well tolerated and manageable, with 29% grade 3 and 10.9% grade 4 toxicities. Median PFS and OS were 4.1 months (CI95% 3.2–4.9) and 11.1 months (CI95% 9.5–14.7), respectively. Triple-negative disease, > 2organs involved and being younger than 70 years old were independent prognosis factors for worse OS in multivariate analysis. Most patients (75%) progressed in pre-existing metastases sites.ConclusionIn everyday clinical practice, eribulin’s efficacy seems similar to pivotal trials. CNS-efficacy was observed. TNBC, > 2 organs involved and being younger than 70 years old were independent prognosis factors for worse OS. Remarkably, less incidence of grade 4-toxicity compared to previous studies was found.

Abstract P4-13-01: Endocrine treatment for hormone receptor-positive advanced breast cancer patients with endocrine-sensitive or endocrine-resistant disease: A systematic review and network meta-analysis

Abstract Background: For patients with hormone receptor-positive (HR+) advanced breast cancer (ABC), the choice of endocrine treatment should be based on the best available evidence. However, no direct head-to-head comparison of all tested regimens is currently available. This network meta-analysis aims at providing detailed inference-based data to guide decision making on endocrine therapy for HR+ ABC patients in two different clinical scenarios: endocrine-sensitive and endocrine-resistant ABC, as defined by the ABC guidelines criteria. Methods: Phase II/III randomized clinical trials published or presented up to June 15, 2018 and comparing two or more different endocrine treatments (with or without associated targeted therapies) for HR+, HER2-negative ABC patients were included, irrespective of treatment line. Relative treatment effects were pooled as hazard ratios (HRs) and modeled in a network meta-analysis using a Bayesian framework with fixed-effects models in order to infer the best approach. The main outcomes were progression-free survival (PFS) and overall survival (OS). Four separate analyses were carried out: PFS and OS networks in both endocrine-sensitive and endocrine-resistant populations. Results: A total of 26 trials were included in this meta-analysis (N=11330 patients). In the endocrine-sensitive setting, 12 trials were included in the PFS network (N=5200 patients; 10 different regimens) and 3 trials in the OS network (N=1295; 3 regimens). In terms of PFS, the combination of Fulvestrant 500 mg (F500)+CDK4/6 inhibitors (CDKi) had a 80% probability of being the most effective treatment, followed by aromatase inhibitor (AI)+CDKi (17% chance of being the best approach). The HR for the comparison between F500+CDKi vs. AI+CDKi was 0.82 (95% credibility interval [CrI] 0.54-1.25). Regarding OS, the AI+CDKi approach had a 63% chance of being the most effective regimen, followed by F500 (36% likelihood) – the comparison between the two regimens yielded a HR of 0.93 (95% CrI 0.61-1.40). In the endocrine-resistant setting, 18 trials were included in the PFS network (N=6130; 20 regimens) and 7 in the OS network (N=2701; 10 regimens). For PFS, F500+CDKi had a 59% probability of being the most effective treatment, followed by F500+Everolimus (11% likelihood). The HR of the comparison between F500+CDKi vs. F500+Everolimus was 0.84 (95% CrI 0.57-1.25). In terms of OS, F500+FGFR inhibitors had a 29% chance of being the best treatment option, followed by AI+everolimus (24% likelihood) – the HR for the comparison of F500+FGFR inhibitors vs. AI+everolimus was 1.07 (95% CrI 0.36-3.18). Conclusion: This network meta-analysis provides for the first time a comparison of all tested treatment options for HR+ ABC patients in both endocrine-sensitive and endocrine-resistant settings. In terms of PFS, F500+CDKi appears to be the best treatment option for both disease settings. As for OS, AI+CDKi is possibly the best choice for endocrine-sensitive ABC patients. Concerning endocrine-resistant disease, F500+FGFR inhibitors may be an effective regimen which should be further studied, while AI+everolimus remains the best available option in this setting. Citation Format: Brandão M, Maurer C, Ziegelmann P, Pondé N, Ferreira AR, Martel S, Piccart-Gebhart M, Debiasi M, de Azambuja E, Lambertini M. Endocrine treatment for hormone receptor-positive advanced breast cancer patients with endocrine-sensitive or endocrine-resistant disease: A systematic review and network meta-analysis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-01.

Abstract P6-18-23: Palbociclib and endocrine therapy in fourth line and beyond for hormone receptor-positive HER2-negative advanced breast cancer: The UK compassionate access program experience

Abstract Background Palbociclib is approved in 1st line for hormone receptor (HR)-positive HER2-negative advanced breast cancer (ABC). A Compassionate Access Program (CAP) previously allowed patients to receive it in 4th line. However, Palbociclib has not been specifically tested in this population. We aimed to determine the safety and efficacy profile of Palbociclib within the CAP across ten institutions in the United Kingdom. Methods We retrospectively identified HR-positive HER2-negative ABC patients on the Palbociclib CAP between December 2015 and September 2017. Demographics, disease characteristics, prior treatments, blood tests, toxicities, treatment delays and responses were recorded. Simple statistics, Fisher's exact test, chi-squared method and Cox regression were used as appropriate. Results 118 patients identified had median age of 59 (32-82). 97 (82.20%) were postmenopausal and 109 (92.37%) had ECOG Performance Status 0-1. 96 (81.36%) had visceral involvement, 19 (16.10%) bony only and 15 (12.71%) visceral only disease. Patients received a median 5 (range 3-11) prior lines of treatment and 3 (range 0-8) prior chemotherapy lines. 105 patients (89.74%) developed neutropenia (grade ≥3 in 59 [56.19%]). 6 experienced febrile neutropenia (5.13%). 57 (48.72%) had a dose reduction, down to 100mg in 48 (41.03%) and 75mg in 9 (7.69%) due to hematologic toxicity in 46 (80.70%). Dose delays were in median 7 days long (range: 0-56). Palbociclib was discontinued due to disease progression in 97 (82.91%) and to toxicity in 5 (4.27%). Grade 3 neutropenia occurred in 45 patients (67.16%) who received ≥3 and in 22 (32.84%) who received <3 prior chemotherapies (p 0.351). Palbociclib produced clinical benefit rate (CBR) of 47.52% and overall response rate of 15.84% in 101 patients assessed. CBR was 45.45% with previous endocrine treatment (ET) progression-free survival (PFS) <6 months versus 49.12% if PFS ≥6 months (p 0.714). Overall, median PFS was 4.5 months (95% CI 3.7-5.9). The PFS seen in different subgroups showed no impact in relation to the number of lines of prior chemotherapy (<3 lines: 5.9 months [95% CI 3.7-11.0]; ≥3 lines: 4.3 months [95% CI 3.3-5.5], p 0.159), but was numerically greater in those who had previous benefit from ET (PFS ≥6 months: 5.9 months [95% CI 4.4-8.0]; <6 months: 3.7 months [95% CI 2.8-4.5], p. 0.055) or in those with bone only disease (bone only: 11.0 months [95% CI 2.3-not reached]; other sites involved: 4.4 months [95% CI 3.6-5.5], p 0.024). Median OS was 15.8 months (95% CI 13.3-18.7) for the whole cohort and it was greater in patients who derived longer PFS from prior ET (≥6 months: 18.1 months [95% CI 13.0-NR]; <6 months: 14.4 months [95% CI 7.7-18.3], p. 0.052). Conclusions To date, this is the most extensive analysis of Palbociclib outcomes in ≥4th-line setting. In this heavily pretreated population clinical benefit was confirmed particularly for endocrine-sensitive disease and predominantly involving the bones and in earlier lines of treatment. Grade ≥3 neutropenia rates were similar to PALOMA trials, but the higher incidence of febrile neutropenia need to be carefully considered. Citation Format: Battisti NML, Kingston B, King J, Denton A, Waters S, Sita-Lumsden A, Rehman F, Stavraka C, Kristeleit H, Sawyer E, Houghton D, Davidson N, Howell S, Choy J, Harper P, Roylance R, Fharat R, Mohammed K, Ring A, Johnston S. Palbociclib and endocrine therapy in fourth line and beyond for hormone receptor-positive HER2-negative advanced breast cancer: The UK compassionate access program experience [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-23.

Palbociclib and endocrine therapy in heavily pretreated hormone receptor-positive HER2-negative advanced breast cancer: the UK Compassionate Access Programme experience.

Palbociclib is approved in 1st line for hormone receptor (HR)-positive HER2-negative advanced breast cancer (ABC). A Compassionate Access Programme previously allowed patients to receive it in 4th line. However, Palbociclib has not been specifically tested in this population. We aimed to determine the safety and efficacy profile of Palbociclib within the Programme across ten institutions in the United Kingdom. We retrospectively identified HR-positive HER2-negative ABC patients on the Programme between December 2015 and September 2017. Demographics, disease characteristics, prior treatments, blood tests, toxicities, treatment delays and responses were recorded. Simple statistics, Fisher's exact test, χ2 method and Cox regression were used. 118 patients identified had a median age of 59. 82.2% were postmenopausal and 92.4% performance status 0-1. 81.4% had visceral involvement and 6.8% bone-only disease after a median of 5 prior treatments and 3 prior chemotherapies. Clinical benefit rate was 47.5%, overall response rate 15.8%, median PFS 4.5 months and median OS 15.8 months. Longer progression-free survival on prior endocrine therapy was a predictor of longer PFS and OS. 89.7% developed neutropenia (grade ≥ 3 in 56.8%). 5.1% experienced febrile neutropenia. 48.3% had dose reductions and 3.4% discontinued Palbociclib following toxicity. No statistically significant difference in grade ≥ 3 neutropenia was observed according to metastatic sites nor previous treatments. This is the most extensive analysis of palbociclib in ≥ 4th-line setting. Clinical benefit was confirmed particularly for endocrine-sensitive, predominantly bony disease and in earlier lines of treatment. Safety was similar to PALOMA trials with higher febrile neutropenia rate.

Abstract OT1-01-02: A multicenter phase II trial to evaluate the efficacy and safety of pembrolizumab and gemcitabine in patients with HER2-negative advanced breast cancer: GEICAM/2015-04 PANGEA-Breast

Abstract Background: Treatment options for advanced breast cancer (ABC) are multiple but unable to properly respond to current clinical needs. In particular, improved therapies are needed for triple negative and hormone receptor (HR)-positive but heavily pretreated patients. Pembrolizumab (P) is a human monoclonal antibody that blocks the PD-1/PD-L1 interaction hence potentiates anticancer T cell responses. Gemcitabine (G) is a cytotoxic drug with well-known immunostimulatory properties. Here, we report an ongoing phase II clinical trial to identify the Recommended Phase II Dose (RP2D) and the efficacy of the combination of these two agents in ABC patients. We hypothesize that these agents may synergize to induce responses with long term clinical benefit (ClinicalTrials.gov Identifier: NCT03025880). Trial Design: Eligible patients are HER2-negative ABC patients who received prior treatment with anthracyclines and taxanes and two or more prior lines of hormone therapy, if HR-positive disease. Patients with CNS involvement are also eligible if clinically stable. Treatment consists of 21-day cycles with 200 mg P on day 1 and G on days 1 and 8. In the safety dose testing, we use a standard 6+6 design with 2 dose levels (DL) of G: 1250 mg/m2 (DL0) and 1000 mg/m2 (DL1). Patients are treated until radiologic or symptomatic progression, or unacceptable toxicity. The primary objectives are RP2D and objective response rate (ORR) of the combination; secondary objectives include evaluation of safety and tolerability and other efficacy variables (progression-free survival [PFS], clinical benefit rate [CBR], response duration [RD] and overall survival [OS]). Efficacy is measured by RECIST 1.1. and irRECIST. Safety is measured using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 4.0. As exploratory objectives, immunological biomarkers are analyzed in tumor biopsies and blood samples and correlated with (1) clinical efficacy and (2) disease outcomes.Sequential tumor samples are collected at baseline, cycle 3 and at progression. Blood samples are drawn at baseline, cycle 3, and cycle 6, or at post-treatment visit (whatever occurs first). Tumor samples are characterized for intratumoral and stromal tumor-infiltrating lymphocytes, tumor-associated macrophages and myeloid-derived suppressor cells, PD-L1 expression in tumor cells and stroma. Moreover, molecular and genetic profiling will be performed. Blood samples are characterized for peripheral blood mononuclear cell (PBMC) phenotype (including expression of co-activatory and co-inhibitory receptors), cytokine profile, and activity of other immunosuppressive pathways (e.g., IDO1-dependent tryptophan catabolism). These results will be compared with data from a cohort of healthy volunteers. A maximum of 65 patients will be included. The study is approved by the ethical committee and Competent Authority of Spain and already open for patient recruitment in 2 of the 10 participating sites. Keywords: Breast HER2 negative Pembrolizumab Immunotherapy Citation Format: de la Cruz L, Sánchez-Margalet V, Berraondo P, Benito S, Escudero MJ, Caballero R, Carrasco E, Galluzzi L, Rojo F. A multicenter phase II trial to evaluate the efficacy and safety of pembrolizumab and gemcitabine in patients with HER2-negative advanced breast cancer: GEICAM/2015-04 PANGEA-Breast [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-01-02.