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Purpose:The stimulator of IFN genes (STING) is a transmembrane protein that plays a role in the immune response to tumors. Single-agent STING agonist MIW815 (ADU-S100) has demonstrated immune activation but limited antitumor activity. This phase Ib, multicenter, dose-escalation study assessed the safety and tolerability of MIW815 plus spartalizumab (PDR001), a humanized IgG4 antibody against PD-1, in 106 patients with advanced solid tumors or lymphomas.Patients and Methods:Patients were treated with weekly intratumoral injections of MIW815 (50–3,200 μg) on a 3-weeks-on/1-week-off schedule or once every 4 weeks, plus a fixed dose of spartalizumab (400 mg) intravenously every 4 weeks.Results:Common adverse events were pyrexia (n = 23; 22%), injection site pain (n = 21; 20%), and diarrhea (n = 12; 11%). Overall response rate was 10.4%. The MTD was not reached. Pharmacodynamic biomarker analysis demonstrated on-target activity.Conclusions:The combination of MIW815 and spartalizumab was well tolerated in patients with advanced/metastatic cancers, including in patients with anti-PD-1 refractory disease. Minimal antitumor responses were seen.

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Introduction: Tumor-Infiltrating Lymphocytes (TILS) is a well-known predictor of response to primary chemotherapy1,2 and a prognostic factor for improved survival in different breast cancer subtypes3. We present data on the association of the level of TILs and morphologic characteristics of such infiltrate with pCR. Material and methods: A series of 477 breast cancer patients (479 tumors) treated with primary chemotherapy at Catalan Institut of Oncolgy - H.U. Bellvitge between January 2009 and December 2016. Chemotherapy consisted on anthracyclines and taxanes (plus trastuzumab if Her-2 positive disease). Levels of percentage of TILs using hematoxylin-eosin-stained sections of diagnostic core-needle biopsy were evaluated according to international guidelines in a prospectively defined retrospective analysis. Characterization of TILS consisted on identification of plasma cells, intraepithelial infiltrate vs stromal infiltrate and homogeneous vs heterogeneous infiltrate. A sub-classification using levels of TILS and heterogeneity was done for statistical purposes. Levels of TILS and their morphological characteristics were examined for their associations with pCR adjusted for predictive clinic-pathological factors, by univariate and multivariate logistic regression, statistical significance set at 0.05. A ROC curve was performed to look for a cut-point of TILs to predict PCR. Results: The mean value of TILs was 23.79% (SD, 24%). TILs were significantly higher in ductal carcinomas (39.1% vs 0%, p=0.007), grade 3 (55.2 vs 17.7%p30 (48.8% vs 24.5%, p 20% (15.2% vs 41.5%, OR: 3.96 [95%CI, 2.57-6.10]; P < 0.001); plasma cells (OR 6.61 [95%CI, 1.51-28.8]; P=0.01), intraepithelial TILS (OR: 10.34 [95%CI, 2.22-48.01]; P =0.003), homogeneous high infiltrate (OR: 13.6 [95%CI, 3.04-60.77]; P =0.001). In luminal tumors, TILs over 20% predicted pCR (OR 12.3 [95%CI, 4.0-37.7]; P < 0.001) as well as in TNBC (OR 4.32 [95%CI, 1.77-10.53]; P=0 .001) but not in those cases with HER2 positive tumors (luminalB HER2 + HER2) (OR 1.65 [95%CI, 0.88-3.07]; P=0.118). In the multivariate analyses, levels of TILs > 20% were associated with higher pCR rates (adjusted odds ratio, 2.44 [95%CI, 1.48-4.01]; P < .001). Conclusions: The presence of TILs over 20% at diagnosis is an independent, positive, predictive marker of pCR in early breast cancer treated with neoadjuvant chemotherapy. Interestingly, the predictive information added by TILs >20% was higher in luminal and triple negative tumors compared to HER2 positive cases. Careful morphological characterization of TILS may add valuable predictive information and can be done in current pathologic laboratories with a well-trained breast cancer pathologist. References: 1.J Clin Oncol 2009; 28:105-113. doi: 10.1200/JCO.2009.23.73702.JAMA Oncol. 2015;1(4):448-454. doi:10.1001/jamaoncol.2015.08303.Lancet Oncol 2018: 19: 40-50 http://dx.doi.org/10.1016/S1470-2045(17)30904-X. N%Age years (mean, sd)Grade*I326.7II19540.7III15152.6Ki 67≤3020442.6>3027557.4Molecular subtype*Luminal A469.6Luminal B HER2 -14329.9Luminal B HER2+9219.2HER+ enriched7615.9Triple negative12225.5Pathologic responseNon-pCR35874.7pCR12125.3 Citation Format: Catalina Falo, Juan Azcarate, Ana Petit, Andrea Vethencourt, Sergi Fernandez Gonzalez, Amparo Garcia-Tejedor, Silvia Vazquez, Hector Perez, Maria Laplana, Charo Taco, Esther Guerra, Anna Guma, Raul Ortega, Agostina Stradella, Sabela Recalde, Adela Fernandez-Ortega, Rafael Villanueva, F Javier Perez, M Jesus Pla, Miriam Campos, Diana Perez, Eulalia Fernandez-Montoliu, Veronica Obadia, Monica Cejuela, Miguel Gil-Gil, Sonia Pernas, Mar Varela, Teresa Soler-Monzo. Morphologic characterization of tumor-infiltrating lymphocytes and its relation with pathological response in a series of breast cancer patients treated with primary chemotherapy [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 P1-08-26.

Background: Most breast cancers (BC) exhibit low immune infiltration and are unresponsive to immunotherapy. Inhibitors of the Receptor Activator of NFkB (RANK) pathway, such as denosumab, used for the treatment of bone metastasis, have been shown to prevent BC, reducing tumor cell proliferation and survival. Our recent data supports that RANK pathway inhibition in BC cells enhances anti-tumor immune response. However, the population of BC patients who may benefit from denosumab remains to be identified. The aim of the study is to evaluate the antiproliferative, proapoptotic and/or immunomodulatory activity of denosumab in early BC and to identify biomarkers of response. Methods: Patients with early stage HER2-negative BC, candidates to tumor excision as first therapeutic approach were included. Patients were randomized 2: 1 to denosumab (two doses of 120mg/Kg subcutaneous denosumab, days 1 and 8 plus oral calcium 1000 mg daily for a month) and control arm (no treatment). Blood and tumor samples were collected at baseline and at surgery (2-4 weeks later). Putative changes in tumor cell proliferation by Ki67 immunohistochemistry (IHC), survival by Cleaved caspase-3 IHC and tumor infiltrating lymphocytes (TILs) quantified in H&E were evaluated between initial biopsy and surgery. RANK and RANKL expression will be analysed by IHC and the infiltrating immune populations will be characterized by specific antibodies (CD3, CD4, CD8, CD20, FoxP3, CD68, PDL1, PD1). We will analyse denosumab driven gene expression changes in tumor samples and tools such as CIBERSORT will be used to characterize the immune infiltrate. To assess the increase in TILs and the variation in Ki 67 and Cleaved caspase-3, the T-test for paired samples was used. A value of p less than 0.05 was defined as statistically significant. Result: We present results from the initial 45 patients enrolled out of 60, 31 cases in the experimental arm and 13 in the control arm. Mean age was 55,97 (range 37-88) years. 38 women with luminal breast cancer were analysed and 7 cases of triple negative BC (5 in experimental arm and 2 in control arm). Clinical and tumor characteristics were well balanced between both groups. No relevant toxicities were reported. There was no reduction of Ki67 in either of the two arms and no changes in Cleaved caspase-3 were observed. Interestingly, a statistically significant increase in TILs was observed in the denosumab treated group (p=0.0092, Paired t test) but not in the control group (p=0.68). 29.03% of patients treated with denosumab showed a ≥10% increase in TILs vs 7.14% in the control group (p=0.13). Denosumab was associated with an effective systemic inhibition of RANKL. No relationship was found between serum RANKL levels at baseline and response to denosumab. RNAseq analysis and immunophenotyping is still in progress. Conclusion: Short term neoadjuvant denosumab induces an immunomodulatory effect with an increase in stromal TILs in early BC. ClinicalTrials.gov Identifier: NCT03691311 Table 1.ResultsBiopsySurgeryKi 67 (mean frequency) Control24.5729.57Ki 67 (mean frequency) Experimental22.3927.90Cleaved caspase 3 (mean area) Control0.260.58Cleaved caspase 3 (mean area) Experimental0.350.42TILs (mean percentage) Control9.3410.29TILs (mean percentage) Experimental8.2913.54TILs incrementControl p=0.68 vs. Experimental p=0.009 Citation Format: Andrea Vethencourt, Eva M Trinidad, Anna Petit, María T Soler-Monsó, Clara Gómez Aleza, Ander Urruticochea, Amparo García-Tejedor, Anna Gumà Martinez, Veronica Obadia, Silvia Vazquez, Rafael Villanueva, Adela Fernánez, Monica Cejuela, Sabela Recalde Penabad, Agostina Stradella, Miguel Gil-Gil, Sonia Pernas, Eva Gonzalez-Suarez, Catalina Falo. First results of the randomized window of opportunity clinical trial D-Biomark: Immunomodulatory effect of denosumab in early breast cancer [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 P2-08-10.

Purpose To evaluate the differences when performing the sentinel lymph node biopsy (SLNB) before or after neoadjuvant endocrine therapy (NET) in breast cancer patients, and the impact of its timing on prognosis. Methods A retrospective cohort study including 91 postmenopausal cases with clinically node-negative and hormone receptor-positive/HER2 negative (HR+/HER2-) breast cancer, treated with NET and SLNB at our institution. SLNB was performed pre-NET until 2014, and post-NET thereafter. Axillary lymph node dissection (ALND) was indicated only in SLNB-macrometastasis, although in selected elderly patients it was omitted. Kaplan-Meier survival curves were obtained in relation to the status of the axilla, and the differences assessed using the log-rank test. Results Between December 2006 and March 2022, SLNB was performed pre-NET in 14 cases and post-NET in 77. SLNB-positivity was similar regardless of whether SLNB was performed before or after NET (35.7% and 37%, respectively), with 2/14 SLN macrometastases in the pre-NET cohort and 17/77 in the post-NET cohort. Only three patients (18.7%) with SLN macrometastasis had > 3 positive nodes following axillary node dissection. The 5-year overall survival and distant disease-free survival were 92.4% and 94.8% respectively, with no significant differences according to SLNB status. Conclusion SLN positivity did not differ according to its timing (before or after NET). Therefore, NET has no effect on lymph node clearance. Furthermore, the prognosis is good regardless of the axillary involvement. Therefore, factors other than axillary involvement may affect the prognosis in these patients.

Purpose: The stimulator of IFN genes (STING) is a transmembrane protein that plays a role in the immune response to tumors. Single-agent STING agonist MIW815 (ADU-S100) has demonstrated immune activation but limited antitumor activity. This phase Ib, multicenter, dose-escalation study assessed the safety and tolerability of MIW815 plus spartalizumab (PDR001), a humanized IgG4 antibody against PD-1, in 106 patients with advanced solid tumors or lymphomas. Patients and Methods: Patients were treated with weekly intratumoral injections of MIW815 (50–3,200 μg) on a 3-weeks-on/1-week-off schedule or once every 4 weeks, plus a fixed dose of spartalizumab (400 mg) intravenously every 4 weeks. Results: Common adverse events were pyrexia (n = 23; 22%), injection site pain (n = 21; 20%), and diarrhea (n = 12; 11%). Overall response rate was 10.4%. The MTD was not reached. Pharmacodynamic biomarker analysis demonstrated on-target activity. Conclusions: The combination of MIW815 and spartalizumab was well tolerated in patients with advanced/metastatic cancers, including in patients with anti-PD-1 refractory disease. Minimal antitumor responses were seen.

Introduction and objectives. Metaplastic breast cancer is an heterogenous and infrequent disease (0.5-2%). Histologically, it is defined by differentiation of neoplastic epithelium into squamous or mesenchymal-like elements. Although they are mainly triple negative tumors, they present a more aggressive course with less response to chemotherapy and worse prognosis. The aim of our study was to characterize the molecular profile and tumor evolution in matched (primary-relapse) samples of patients (pts) with metaplastic breast cancer. Material and Methods. Genomic profiling of tumor biopsies from different time points in patients with early-stage metaplastic breast cancer who had disease recurrence/progression, and were treated at our institution between 2010 and 2020. Tumor samples were analyzed by DNA- Next Generation Sequencing (NGS; Illumina 2x75bp) using the ActionOncoKitDX panel (Imegen-Health in Code group). It allowed the study of point mutations in 50 genes, CNVs, fusion genes among 8 genes and pharmacogenetic SNPs associated with treatment efficacy or toxicity. It also determined MSI through 110 markers. The results were classified following the recommendations of the ACMG (American College of Medical Genetics). Only pathogenic and likely pathogenic variants were considered for analysis and afterwards we categorized them following the ComPerMed (The Personalized Medicine Commission) criteria. Results. We have analyzed 21 matched diagnosis-relapse tumor samples (8 primary tumor samples, and 13 loco-regional or metastatic disease) from 8 patients. In 4 patients, genomic characterization was performed at 3 different time points of their tumor evolution. Pathogenic alterations identified were mutations in TP53 (in 100% of the samples), TERT promoter (29%), and MYC amplifications (24% of samples, of which 75% were relapse/progression samples). We didn’t find any mutation in PI3KCA, but PTEN was found to have variations in 38% samples (10% mutations and 38% deletions). Amplification of FGFR1 was identified in 13% of the pts (only in the primary tumor). No ERBB2 or EGFR gene amplifications were detected, neither high grade MSI. We did not find a significant increase in point mutations between primary and relapse/progression samples, although gene amplifications were found more frequently in the former ones. Sixty three percent of the cases were Tier I and II category alterations, which could have future implications in the management of this neoplasia. Conclusion. In our series of metaplastic carcinoma, the most frequent pathogenic alterations occurred in cycle regulation’s genes, including TP53 and TERT promoter mutations, and MYC amplifications. Relapse/progression samples were enriched in MYC amplification and inTP53 allelic frequency. Larger studies are required to better characterize these tumors, and identify new strategies to improve the prognosis of these patients. Citation Format: Mónica Cejuela, Agostina Stradella, Anna Petit, Pablo Gargallo, Jan Bosch, Paula Carbonell, Sabela Recalde, Andrea Vethencourt, Adela Fernández, Catalina Falo, Miguel Gil-Gil, Silvia Vazquez, Rafael Villanueva, Teresa Soler, Inés Calabria, Sonia Pernas. Genomic characterization and tumor evolution in matched(primary-relapse)samplesof patients with METAPLASTIC breast cancer [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 P5-07-06.

Summary Background Several de-escalation approaches are under investigation in patients with HER2-positive, early-stage breast cancer. We assessed early metabolic responses to neoadjuvant trastuzumab and pertuzumab using 18F-fluorodeoxyglucose (18F-FDG)-PET (18F-FDG-PET) and the possibility of chemotherapy de-escalation using a pathological response-adapted strategy. Methods We did a multicentre, randomised, open-label, non-comparative, phase 2 trial in 45 hospitals in Spain, France, Belgium, Germany, the UK, Italy, and Portugal. Eligible participants were women aged 18 years or older with centrally confirmed, HER2-positive, stage I–IIIA, invasive, operable breast cancer (≥1·5 cm tumour size) with at least one breast lesion evaluable by 18F-FDG-PET, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a baseline left ventricular ejection fraction of at least 55%. We randomly assigned participants (1:4), via an interactive response system using central block randomisation with block sizes of five, stratified by hormone receptor status, to either docetaxel (75 mg/m2 intravenous), carboplatin (area under the concentration–time curve 6 mg/mL per min intravenous), trastuzumab (subcutaneous 600 mg fixed dose), and pertuzumab (intravenous 840 mg loading dose, 420 mg maintenance doses; group A); or trastuzumab and pertuzumab (group B). Hormone receptor-positive patients allocated to group B were additionally given letrozole if postmenopausal (2·5 mg/day orally) or tamoxifen if premenopausal (20 mg/day orally). Centrally reviewed 18F-FDG-PET scans were done before randomisation and after two treatment cycles. Patients assigned to group A completed six cycles of treatment (every 3 weeks) regardless of 18F-FDG-PET results. All patients assigned to group B initially received two cycles of trastuzumab and pertuzumab. 18F-FDG-PET responders in group B continued this treatment for six further cycles; 18F-FDG-PET non-responders in this group were switched to six cycles of docetaxel, carboplatin, trastuzumab, and pertuzumab. Surgery was done 2–6 weeks after the last dose of study treatment. Adjuvant treatment was selected according to the neoadjuvant treatment administered, pathological response, hormone receptor status, and clinical stage at diagnosis. The coprimary endpoints were the proportion of 18F-FDG-PET responders in group B with a pathological complete response in the breast and axilla (ypT0/is ypN0) as determined by a local pathologist after surgery after eight cycles of treatment, and 3-year invasive disease-free survival of patients in group B, both assessed by intention to treat. The definitive assessment of pathological complete response was done at this primary analysis; follow-up to assess invasive disease-free survival is continuing, hence these data are not included in this Article. Safety was assessed in all participants who received at least one dose of study drug. Health-related quality-of-life was assessed with EORTC QLQ-C30 and QLQ-BR23 questionnaires at baseline, after two cycles of treatment, and before surgery. This trial is registered with EudraCT (2016-002676-27) and ClinicalTrials.gov ( NCT03161353 ), and is ongoing. Findings Between June 26, 2017, and April 24, 2019, we randomly assigned 71 patients to group A and 285 to group B. Median follow-up was 5·7 months (IQR 5·3–6·0). 227 (80%) of 285 patients in group B were 18F-FDG-PET responders, of whom 86 (37·9%, 95% CI 31·6–44·5; p Interpretation 18F-FDG-PET identified patients with HER2-positive, early-stage breast cancer who were likely to benefit from chemotherapy-free dual HER2 blockade with trastuzumab and pertuzumab, and a reduced impact on global health status. Depending on the forthcoming results for the 3-year invasive disease-free survival endpoint, this strategy might be a valid approach to select patients not requiring chemotherapy. Funding F Hoffmann-La Roche.

Brain metastases (BM) occur in 15–35% of patients with metastatic breast cancer, conferring poor prognosis and impairing quality of life. Clinical scores have been developed to classify patients according to their prognosis. We aimed to check the utility of the Breast Graded Prognostic Assessment (B-GPA) and its modified version (mB-GPA) and compare them in routine clinical practice. This is an ambispective study including all patients with breast cancer BM treated in a single cancer comprehensive center. We analyzed the overall survival (OS) from BM diagnosis until death. The Kaplan–Meier method and Cox proportional hazard regression model were used in the analyses. ROC curves were performed to compare both scores. We included 169 patients; median age was 50 years. HER2-positive and triple negative patients were 33.7% and 20.7%, respectively. At the last follow-up, 90% of the patients had died. Median OS was 12 months (95% confidence interval 8.0–16.0 months). OS was worse in patients with > 3 BM and in patients with triple negative subtype. In our series, we confirm that B-GPA and mB-GPA scores correlated with prognosis. ROC curves showed that B-GPA and mB-GPA have similar prognostic capabilities, slightly in favor of mB-GPA.

To find a group of cN2 patients or patients with high axillary burden who become ypN0 after neoadjuvant chemotherapy (NACT) and who may benefit from avoiding a lymphadenectomy. A retrospective observational cohort study was conducted with 221 clinically staged N2 patients or patients with at least 3 suspicious lymph nodes found by ultrasound at diagnosis. The predictive factors for ypN0 analysed were age, MRI-determined tumour size, histological subtype, the Nottingham histologic grade, surrogate molecular subtype, ki-67 and vascular invasion when present. Clinical and radiological responses after NACT were also evaluated. Univariate and multivariate analyses by logistic regression were performed. Distant disease-free survival (DDFS) was calculated in relation to the status of the axillary lymph nodes after NACT. After NACT, 89 patients (40.3%) had axillary pathologic complete response (pCR) (ypN0) and 132 (59.7%) had residual axillary disease (ypN+). Molecular surrogate subtype, Ki-67 expression, and the clinical and radiological responses to NACT were the only independent factors associated with ypN0. Axillary pCR was observed more often in HER2-positive and triple-negative tumours than in luminal ones (OR 7.5 and 3.6, respectively). DDFS was 88.7% (95% CI 80.7–96.7%) for ypN0 and 56.2% (95% CI 32.1–80.3%) for ypN+ (p = 0.09). In HER2-positive and triple-negative breast cancer patients staged as cN2 or with high axillary burden before NACT, a sentinel lymph node biopsy after NACT could be recommended if there is a clinical and radiological response.

Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. Tesetaxel is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and once every 3 week (Q3W) dosing; no observed hypersensitivity reactions; preclinical evidence of central nervous system (CNS) penetration; and improved activity against chemotherapy-resistant tumors. More than 600 patients have been treated with tesetaxel in clinical studies. Tesetaxel had robust monotherapy activity in a Phase 2 study in 38 patients with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45%. CONTESSA TRIO investigates tesetaxel plus 3 different PD-(L)1 inhibitors in patients with TNBC and tesetaxel monotherapy in elderly patients with HER2- MBC. Trial design: CONTESSA TRIO is a 2-cohort, multinational, multicenter, Phase 2 study. In Cohort 1, 90 patients (with potential expansion to up to 150 patients) with metastatic TNBC who have not received prior chemotherapy for advanced disease will be randomized 1:1:1 to receive tesetaxel at 27 mg/m2 Q3W plus either: (1) nivolumab at 360 mg Q3W; (2) pembrolizumab at 200 mg Q3W; or (3) atezolizumab at 1,200 mg Q3W. Nivolumab and pembrolizumab (PD-1 inhibitors) and atezolizumab (a PD-L1 inhibitor) are approved for the treatment of multiple types of cancer; atezolizumab, in combination with nab-paclitaxel, was recently approved in the U.S. for the treatment of metastatic TNBC. The dual primary endpoints for Cohort 1 are ORR and progression-free survival (PFS). A sample size of 30 patients in each PD-(L)1 inhibitor treatment group has approximately 70% power to detect an ORR difference of 35% or greater between the treatment group with the highest ORR and the treatment group with the lowest ORR. An increase in the sample size to 50 patients in each treatment group will increase the power to approximately 85%. Secondary endpoints include duration of response (DoR) and overall survival (OS). Efficacy results for each of the 3 PD-(L)1 inhibitor combinations will be assessed for correlation with the results of each of the 3 approved PD-L1 diagnostic assays. CONTESSA TRIO is the first randomized clinical study to compare 3 approved PD-(L)1 inhibitors. In Cohort 2, 40 elderly patients (with potential expansion to up to 60 patients) with HER2- MBC who have not received prior chemotherapy for advanced disease will receive tesetaxel monotherapy at 27 mg/m2 Q3W. The primary endpoint for Cohort 2 is ORR. A sample size of 40 will allow the ORR to be estimated with a maximum standard error of < 8%. An increase in the sample size to 60 patients will decrease the maximum standard error to < 6.5%. Secondary endpoints include PFS, DoR and OS. Patients with CNS metastases are eligible for both cohorts. The Study was initiated in March 2019. For further information on this trial, email joconnell@odonate.com or visit clinicaltrials.gov (NCT03952325). Citation Format: Sara Tolaney, Joanne Blum, Igor Bondarenko, Arlene Chan, Noshir DaCosta, Yin-Hsun Feng, Yann Izarzugaza, Sung-Bae Kim, Mei-Ching Liu, Maria Eva Peréz Lopéz, Mafalda Oliveira, Samuel Guan Wei Ow, Michel Pavic, Hope Rugo, Lee Schwartzberg, Agostina Stradella, Stew Kroll, Joseph O'Connell, Thomas Wei, Elizabeth Mittendorf. CONTESSA TRIO: A multinational, multicenter, phase 2 study of tesetaxel plus 3 different PD-(L)1 inhibitors in patients with metastatic triple-negative breast cancer (TNBC) and tesetaxel monotherapy in elderly patients with HER2- metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-08-08.

EO2401 includes microbial-derived, synthetically produced HLA-A2 restricted peptides with molecular mimicry to antigens (IL13Rα2, BIRC5 and FOXM1) upregulated in glioblastoma, and the CD4 helper peptide UCP2. Patients with glioblastoma at first progression received EO2401 (300µg/peptide, q2weeks x4 then q4weeks), EO2401+nivolumab (3mg/kg q2weeks), or E02401+nivolumab+bevacizumab (10mg/kg q2weeks). Cohort-1 included EO2401x2 then EO2401+nivolumab. EO2401+nivolumab was evaluated in Cohort-2a, as adjuvant treatment in Cohort-2b, and as neoadjuvant/adjuvant treatment in Cohort-2c. Cohort-3 assessed EO2401+nivolumab+bevacizumab. Part 1 included 40 patients (Cohort-1/3, Cohort-2a/23, Cohort-2b/3, Cohort-3/11). Part 2 allowed low-dose-bevacizumab (5mg/kg q2weeks) for symptomatic edema and enrolled 38 patients (Cohort-1/18, Cohort-2a/15, Cohort-2b/3; and recruiting Cohort-2c/2 target 6, Cohort-3/0 target 15).Safety assessment of part 1 showed EO2401+nivolumab+/-bevacizumab to be well tolerated with EO2401 associated toxicity limited to local administration site reactions (48%; all grade 1-2). The nivolumab-/bevacizumab-toxicity was consistent with historical single-agent data. Strong CD8 T cell ELISPOT responses against the 3 vaccine peptides and cross-reactivity against targeted antigens was demonstrated in the majority of evaluable patients. Immune response was confirmed with tetramer staining of specific CD8 either ex vivo or after in vitro stimulation. For part 1, median progression-free survival (mPFS), and median survival (mOS) for EO2401+nivolumab (Cohorts-1/2/2b, n=29 median follow-up [mFU] 14.0 months) were 1.8 and 10.6 months. Patients on EO2401+nivolumab+bevacizumab (n = 11 mFU 9.6 m) had mPFS 5.5 months and 9 patients alive 7-12.4 months. Objective Response Rate/Disease Control Rate for EO2401+nivolumab and EO2401+nivolumab+bevacizumab was 10%/34% and 55%/82%.Median treatment duration for Cohort-2a part 1 was 6.1 weeks (1/23 on treatment), while it was 10.0 weeks (8/15 on treatment) for Cohort-2a part 2. Overall, in part 2, 36% received low-dose-bevacizumab.EO2401 generated strong immune responses and was well tolerated. Addition of standard bevacizumab to EO2401+nivolumab improved PFS and tumor response. Symptom driven low-dose-bevacizumab supported longer treatment durations. Outcome of study part 2 will be presented.

Metaplastic breast carcinomas are a rare and heterogeneous group of tumors (0.5-2%). They are mainly triple negative tumors but they present poorer chemotherapy responses and worse prognosis than other triple negative tumors. The aim of our study was to characterize the molecular profile and tumor evolution in matched (primary-relapse) tumor samples from patients with early-stage metaplastic breast carcinomas who had disease recurrence/progression. We performed genomic profiling of tumor biopsies at least from two different time points of their tumor evolution. Tumor samples were analyzed by DNA-Next Generation Sequencing (Illumina 2 x 75bp) using the Action OncoKitDX panel (Imegen-Health in Code group), which includes point mutations in 50 genes, CNVs, and fusion genes. Only pathogenic and likely pathogenic variants were considered for analysis and they were categorized following the ComPerMed criteria. We analyzed 21 matched tumor samples (8 primary and 13 relapse/progression samples). Genomic profiling of matched tumor samples revealed that mutations present in primary tumors are generally maintained in the relapse/disease progression. We did not find a significant increase in point mutations between primary and relapse/progression samples, although gene amplifications were found more frequently in relapse/progression samples. Tumor samples harbored high frequency of TP53 (100%) and TERT promoter (29%) mutations, and of MYC amplifications (80% of which in relapse/progression samples). No PI3KCA mutations were found, but PTEN variations were enriched in 38% of samples (10% mutations and 28% deletions). FGFR1 amplifications were identified in 13% of samples (primary tumor only). Neither ERBB2 nor EGFR gene amplifications were detected. The most frequent pathogenic alterations occurred in cycle regulation's genes, including TP53 and TERT promoter mutations, and MYC amplifications. Relapse/progression samples were highly enriched for MYC amplification. Larger studies are required to better characterize these tumors, and identify new strategies to improve the prognosis of these patients.

Introduction Benefit from adjuvant chemotherapy (CT) is doubtful in a high percentage of patients with early breast cancer. The 21-gene recurrence-score (RS) assay (Oncotype DX, Genomic Health) is one gene-expression assay that provide prognostic and predictive information in hormone-receptor (RH) positive breast cancer. The results of the TAILORx study have confirmed that the majority of patients with tumors RH + and HER2 negative can avoid CT without increasing their risk of relapse. From 2012 to 2015 we used Mammaprint (MMP), in our institution and 60% of cases could avoided CT (communicated in SABCS 2015). Since 2017 we use RS for this purpose. Primary Objective To analyze the impact of using RS to change the indication of adjuvant CT. Secondary Objectives To analyze the association between different clinical pathological factors and the RS value, and calculate the difference between the cost of all RS test and the cost in direct expense of the treatment with CT of all patients who could avoid it thanks to the RS Material and methods We analyzed all RS test performed in the three ICO centers during 2017. We sent 112 tumor samples; in 2 samples adequated RNA for RS was not obtained. We compared the adjuvant treatment initially planned according to institutional treatment protocol with the treatment given after RS. We compared the direct economic costs of CT with the costs of the diagnostic test, and performed a logistic regression analysis of some pathological factors and RS value. Results The RS could be determined in 110 of 112 cases, in which there was indication of adjuvant CT. Only 14 patients received CT (12,72%) with the RS value, so CT was avoided in 96 patients (87,28%). The clinical-pathological characteristics of the series are summarized in the table 1. Of the risk factors analyzed, only grade 3 (p 0.001) and PR 25. No association was found between age, nodal status, tumor diameter, Ki67, Infiltrating Ductal Carcinoma vs neither Infiltrating Lobular Carcinoma nor Lympho-Vascular invasion. The cost of the genetic studies was 180000€ (1636€ each). The cost of each CT schedule (EC x 4 followed by paclitaxel x 12) was 7214€ and the total cost of 96 cases 692590€. Direct costs savings estimated from the reduction in CT treatment were 512590€ Conclusion: Our series shows that RS avoided unnecessary CT in 87% of cases and was more cost-effective than a previous series with MMP. G3 and RP 25. Table 1.Patients characteristics and clinical-pathological details from the analyzed tumorsPatient characteristicsAge, mean (range)53,76 (19 – 75)≥50y72 (65.5%) Citation Format: Ferrer M, Dorcas J, Quiroga V, Margelí M, del Barco S, Stradella A, Petit A, Falo C, Viñas G, Romeo M, Villanueva R, Cirauqui B, Vázquez S, Fernández A, Recalde S, Vethencourt A, Soler T, Pérez-Martín X, Gil-Gil M. Impact of oncotype dx genetic signature used in early breast cancer. Clinical and economic analisys of a 110 patient cohort treated in the Catalan Oncologic Institute (ICO), Spain [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 P5-15-09.

2034 Background: EO2401 (EO) was designed to activate existing commensal memory T-cells cross-reacting with tumor associated antigens (TAAs). EO includes microbial-derived, synthetically produced peptides corresponding to HLA-A2 restricted epitopes with molecular mimicry to three TAAs upregulated in glioblastoma (GB), IL13Rα2, BIRC5 and FOXM1, with the CD4 helper peptide UCP2 and the adjuvant Montanide. Pre-clinically EO generates strong immune responses and cross-reactive CD8 cells recognizing the TAAs. Methods: This ongoing Ph 1/2 trial (NCT04116658) investigates EO (SC q2 wks X 4 then q4 wks), EO with nivolumab (3 mg/kg q2 wks; EN), and EN with bevacizumab (10 mg/kg q2 wks; ENB) among four Cohorts (Cs) of pts with GB at first progression after radiotherapy/temozolomide. After the Ph 1 of EO followed by EN (C1), C2 investigated EN without (C2a) or with (C2b) surgery while C3 investigated ENB (population as C2a). Results: Among 40 treated pts (C1 n = 3, C2a n = 23, C2b n = 3, C3 n = 11), median age was 60, 53% male, 40% had KPS 90-100% and 35% had O6-methylguanine DNA-methyltransferase promotor hypermethylated tumors. All evaluable pts demonstrated strong CD8 T-cell ELISPOT responses against the 3 vaccine peptides, with tetramer staining of specific CD8 detected in 24/25 investigated pts after in vitro stimulation and in 19/20 pts directly ex vivo. Cross-reactivity against targeted TAAs was confirmed in 20/21 pts. Majority of response were detected by week 4 after 1st dose and as early as 2 weeks for some pts. EO, EN, and ENB were well tolerated (max exposure EN 68 wks, ENB 30 wks) with EO associated toxicity limited to local administration site reactions (48%; grade 1-2). The frequency and severity of nivolumab- or bevacizumab-associated AEs was consistent with historical monocompound experience. With a median follow-up of 9.3 months (range, 2.8-15.6), median progression-free survival (PFS), survival at 6 months (OS-6) and at 12 months for EN (C1+C2a+C2b) were 1.8 months (3 ongoing at 5.9, 7.1, and 14.7 months), 85%, and 50.1% (19/29 alive), respectively. With a median follow-up of 3.7 months (range, 2.2-7.2), pts on ENB (C3) have median PFS and OS-6 of 5.5 months (7 ongoing), and 80% (10/11 alive), respectively. ORR for EN and ENB were 10% and 36%, respectively (5 of 7 ongoing). In C2a, 12/23 pts stopped treatment due to neurological symptoms and PD on first MRI (median 5 wks, range 2-8). In C3 (ENB), only 1/11 pts stopped early due to PD. Conclusions: EO2401 generated strong systemic immune responses and was well tolerated in combination with nivolumab +/- bevacizumab. The addition of bevacizumab to EN improved PFS while survival across treatment cohorts is pending ongoing follow-up. To prolong EN exposure that is likely required for therapeutic activity in recurrent GB, the trial has been expanded with additional pts to evaluate low-dose bevacizumab (5 mg/kg q2 wks up to x 6) for early progressive neurological symptoms. Clinical trial information: NCT04116658.

2581 Background: The overall survival (OS) benefit observed with immune checkpoint inhibitors led to their approval in many tumor types. Given the large number of IT compounds in early clinical development, many pts are offered IT within Ph1-CT even before having exhausted standard of care (SOC) therapies. We assessed outcomes of pts receiving novel IT treatments within Ph1-CT at the Phase 1 Unit of Catalan Institute of Oncology (ICO), Barcelona, Spain. Methods: We retrospectively reviewed a correlative series of pts with advanced/metastatic solid tumors treated with IT within Ph1-CT at ICO from January 2018 to June 2021. Primary endpoint was to assess clinical outcomes measured by median progression-free survival (mPFS) and median OS (mOS) according to number of prior lines (PL) for recurrent/metastatic disease, grade 3-4 toxicity (G3-4 Tox) and age. Data on prior IT (yes vs no) and availability of alternative SOC were evaluated. Overall response rate (ORR) was assessed according to RECIST 1.1. Clinical benefit rate (CBR) was defined as complete/partial response + stable disease for ≥6 months (m). PFS/OS were calculated by Kaplan-Meier method. Log-rank test was used for comparisons. Median PFS of alternative SOC according to historical data was recorded by tumor type and line of treatment. Results: A total of 104 pts received IT within Ph1-CT: IT monotherapy = 39 (37.5%), IT combinations = 65 (62.5%) (IT+IT = 59 [90.8%], IT+targeted therapy = 6 [9.2%]). Median age was 54 y (42-77), 62.5% were men and all had ECOG 0-1. Four most frequent cancers were urothelial (19.2%), colorectal (15.3%), head & neck (12.5%) and glioblastoma (11.5%). Number of PL: 0 = 20 (19.2%) pts, 1 = 37 (35.6%) pts, ≥2 = 47 (45.2%) pts. Nine (8.6%) pts had received prior IT. G3-4 Tox rate for the overall population was 19.2% and for pts who had received prior IT was 33%. ORR was 11.5%; CBR was 24%. Overall mPFS and mOS were 2.7m and 8.6m, respectively. Pts with less PL had greater mPFS and mOS (p < 0.05) (Table). Pts with available alternative SOC had lower mPFS but similar mOS compared to historical SOC (2.6m vs 4.8m, 11.4m vs 11.8m, respectively). G3-4 Tox (yes vs no) and age ( < 70 vs ≥70) did not significantly impact on mOS or mPFS (p = 0.18 and p = 0.83, respectively). At end of Ph1-CT treatment, 47 (45.2%) pts worsened their ECOG status, 15 (14.4%) pts were enrolled in a subsequent trial and 22 (21.1%) pts received SOC. Conclusions: In our cohort of pts treated with novel IT within Ph1-CT, overall clinical outcomes were modest in terms of mPFS, mOS, and CBR. However, pts with less pre-treated tumors seem to achieve higher survival benefit from early treatment with IT within Ph1-CT, although this benefit remains unclear in pts with alternative SOC. [Table: see text]

e14549 Background: Immuno-Oncology (IO) has revolutionized anticancer therapeutics and changed the early drug development paradigm. Positive results and limited access to IO drugs in some countries have led to increased enrollment in IO Ph1-CT at an earlier timepoint in patients (pts) disease journey. We evaluated the impact of IO era on enrollment patterns in Ph1-CT. Methods: We retrospectively reviewed pts with recurrent/metastatic solid tumors enrolled in Ph1-CT from January 2018 to June 2021 at the Phase 1 Unit of Catalan Institute of Oncology (ICO), Barcelona, Spain. The primary goal was to assess Ph1-CT enrollment patterns, including use of molecular pre-screening/personalized drug matching, and the availability of alternative standard of care (SOC). Overall response rate (ORR) was assessed according to RECIST 1.1. Clinical benefit rate (CBR) was defined as complete/partial response+stable disease for ≥6 months. Median progression-free survival (mPFS) and overall survival (mOS) using Kaplan-Meier method were provided. Results: A total of 175 pts were enrolled in Ph1-CT. Median age was 54 years (range 43-75), Male:Female = 99:76, 99% had ECOG 0-1. The most prevalent tumors were: 32 (18%) breast, 31 (18%) colorectal, 25 (14%) urogenital and 23 (13%) glioblastoma multiforme. One hundred forty-six (83%) pts were enrolled in Ph1-CT with IO (alone or in combination) and 29 (17%) pts with targeted therapy (TT). Molecular pre-screening tests were required in 24 (14%) pts (22 pts IO vs 2 pts TT trial). Eleven (42%) pts were pre-screening failures. Screening failure (SF) rate was 19%, the main reason being clinical worsening for 7 (4%) pts. Thirty-three (19%) pts had an alternative SOC treatment available at time of enrollment. One hundred two (58%) pts had received ≤1 prior lines and 26 (89%) were IO-naïve. Finally, 129 (74%) out of 175 pts enrolled were treated within Ph1-CT. Out of 129 treated pts, ORR was achieved in 18 (14%) pts (3% complete response) and 44 (34%) had stable disease. CBR was observed in 36 (28%) pts. mPFS was 2.8 months and mOS was 10.9 months. Toxicity grade 3-4 occurred in 25 (19%) of pts and 6 (5%) pts had to interrupt treatment. Seventy-one (55%) pts received subsequent therapies: 22 (17%) in Ph1-CT; 49 (38%) SOC. Eleven (9%) pts received IO as subsequent therapy. Decline in ECOG status (baseline vs end of treatment) occurred in 65 (50%) pts. Conclusions: In our cohort of Ph1CT pts, there has been an increasing number of pts enrolled in IO trials compared to TT. Most pts received treatment within Ph1-CT at an earlier timepoint in the course of their disease (1st or 2nd lines). Our results suggest a clear impact of the IO era on the trends of Ph1-CT availability and enrollment patterns.

The METTEN study assessed the efficacy, tolerability, and safety of adding metformin to neoadjuvant chemotherapy plus trastuzumab in early HER2-positive breast cancer (BC). Women with primary, non-metastatic HER2-positive BC were randomized (1:1) to receive metformin (850 mg twice-daily) for 24 weeks concurrently with 12 cycles of weekly paclitaxel plus trastuzumab, followed by four cycles of 3-weekly FE75C plus trastuzumab (arm A), or equivalent regimen without metformin (arm B), followed by surgery. Primary endpoint was the rate of pathological complete response (pCR) in the per-protocol efficacy population. pCR rate was numerically higher in the metformin-containing arm A (19 of 29 patients [65.5%, 95% CI: 47.3–80.1]) than in arm B (17 of 29 patients [58.6%, 95% CI: 40.7–74.5]; OR 1.34 [95% CI: 0.46–3.89], P = 0.589). The rate of breast-conserving surgery was 79.3% and 58.6% in arm A and B (P = 0.089), respectively. Blood metformin concentrations (6.2 μmol/L, 95% CI: 3.6–8.8) were within the therapeutic range. Seventy-six percent of patients completed the metformin-containing regimen; 13% of patients in arm A dropped out because of metformin-related gastrointestinal symptoms. The most common adverse events (AEs) of grade ≥3 were neutropenia in both arms and diarrhea in arm A. None of the serious AEs was deemed to be metformin-related. Addition of anti-diabetic doses of metformin to a complex neoadjuvant regimen was well tolerated and safe. Because the study was underpowered relative to its primary endpoint, the efficacy data should be interpreted with caution.

To report the outcomes of implementing the ACOSOG Z0011 and AMAROS trials relevant to clinical practice, and to define target groups in whom to avoid or recommend axillary radiotherapy (ART). We also aimed to analyse the reduction in morbidity when axillary lymph node dissection (ALND) was omitted. A retrospective cohort study of T1–T2 patients with macrometastases at sentinel lymph node (SLN) who were treated between 2011 and 2020. Breast surgery included either lumpectomy or mastectomy. Patients with ≤ 2 positive SLN were divided into two cohorts by whether they received ART or not. Survival outcomes and morbidity were analysed by Kaplan–Meyer curves and Cox-regression, respectively. 260 pN1a patients were included and ALND was avoided in 167 (64.2%). According the Z0011 results, 72 (43.1%) received no further ART; and based on AMAROS criteria 95 (56.9%) received ART. Median follow-up was 54 months. The 5-year overall survival was 96.8% in the non-RT cohort and 93.4% in the RT cohort (p = 0.19), while the respective 5-year disease-free survivals were 100% and 92.3% (p = 1.06). Lymphedema developed in 3.6% of patients after SLNB versus 43% after ALND (OR 20.25; 95%CI 8.13–50.43). Decreased upper-extremity range of motion appeared in 8.4% of patients after SLNB versus 31.2% after ALND (OR 4.95; 95%CI 2.45–9.98%). Our study confirms that omitting ALND is safe and has high survival rates in patients with T1–T2 tumours and ≤ 2 positive SLNs. Adding ART could be a treatment option for patients who present other risk factors. Avoiding ALND with or without ART was associated with significantly less arm morbidity.

Background In the phase III OlympiAD trial, olaparib significantly increased progression-free survival (PFS) compared with chemotherapy of physician's choice in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (mBC). The phase IIIb LUCY trial assessed the clinical effectiveness of olaparib in similar patients, in a setting reflecting clinical practice. Methods This open-label, single-arm trial of olaparib (300 mg, twice daily) enrolled patients with BRCAm, HER2-negative mBC who had received taxane and/or anthracycline in the (neo)adjuvant/metastatic setting and not more than two lines of prior chemotherapy for mBC. Patients with hormone receptor–positive mBC had progressed on at least one line of endocrine therapy in an adjuvant/metastatic setting and were unsuitable for further endocrine treatment. This interim analysis was planned after 160 PFS events. Results Of 563 patients screened, 252 patients with gBRCAm were enrolled and received at least one dose of olaparib. The median investigator-assessed PFS was 8.11 months (95% confidence interval [CI], 6.93–8.67; 166/252 events [65.9% maturity]). The investigator-assessed clinical response rate was 48.6%, and median time to first subsequent treatment or death was 9.66 months (95% CI, 8.67–11.14). The most common treatment-emergent adverse events (TEAEs; >20% patients) were nausea, anaemia, asthenia, vomiting and fatigue. Eleven patients (4.4%) discontinued treatment because of a TEAE. Grade 3 or higher TEAEs occurred in 64 patients (25.4%), including anaemia (33 patients; 13.1%). Conclusion Olaparib was clinically effective in patients with gBRCAm, HER2-negative mBC with safety outcomes consistent with previous findings. ClinicalTrials.gov identifier: NCT03286842 .

Background: CHEK2 variants are associated with intermediate breast cancer risk among other cancers. We aimed to comprehensively describe CHEK2 variants in a Spanish hereditary cancer (HC) cohort and adjust American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines for their classification. Methods: First, three CHEK2 frequent variants were screened in a retrospective Hereditary Breast and Ovarian Cancer cohort of 516 patients. After, the whole CHEK2 coding region was analyzed by next-generation sequencing in 1,848 prospective patients with HC suspicion. We refined ACMGAMP criteria and applied different combinatorial rules to classify CHEK2 variants and define risk alleles. Results: We identified 10 CHEK2 null variants, 6 missense variants with discordant interpretation in ClinVar database, and 35 additional variants of unknown significance. Twelve variants were classified as (likely)-pathogenic; 2 can also be considered “established risk-alleles” and one as “likely risk-allele”. The prevalence of (likely)-pathogenic variants in the HC cohort was 0.8% (1.3% in breast cancer patients and 1.0% in hereditary non-polyposis colorectal cancer patients). Conclusions: Here we provide ACMG adjustment guidelines to classify CHEK2 variants. We hope that this work would be useful for variant classification of other genes with low effect variants

Background CHEK2 variants are associated with intermediate breast cancer risk among other cancers. We aimed to comprehensively describe CHEK2 variants in a Spanish hereditary cancer (HC) cohort and adjust American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines for their classification. Methods First, three CHEK2 frequent variants were screened in a retrospective Hereditary Breast and Ovarian Cancer cohort of 516 patients. After, the whole CHEK2 coding region was analyzed by next-generation sequencing in 1,848 prospective patients with HC suspicion. We refined ACMG-AMP criteria and applied different combined rules to classify CHEK2 variants and define risk alleles. Results We identified 10 CHEK2 null variants, 6 missense variants with discordant interpretation in ClinVar database, and 35 additional variants of unknown significance. Twelve variants were classified as (likely)-pathogenic; two can also be considered "established risk-alleles" and one as "likely risk-allele". The prevalence of (likely)-pathogenic variants in the HC cohort was 0.8% (1.3% in breast cancer patients and 1.0% in hereditary non-polyposis colorectal cancer patients). Conclusions Here we provide ACMG adjustment guidelines to classify CHEK2 variants. We hope that this work would be useful for variant classification of other genes with low effect variants. This article is protected by copyright. All rights reserved.

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Background: Several de-escalation approaches are under investigation in patients with HER2-positive early breast cancer (EBC). We assessed early metabolic responses to neoadjuvant trastuzumab and pertuzumab (HP) using 18F-FDG PET/CT (FDG-PET) and the possibility of chemotherapy de-escalation using a response–adapted strategy. Methods: PHERGain is a randomised, open-label phase 2 trial conducted in 45 centres from seven European countries. Patients aged ≥18 years with FDG-PET–evaluable, centrally confirmed HER2-positive EBC were randomly allocated (1:4) to receive docetaxel (T), carboplatin (C), and HP (arm A) or HP±endocrine therapy (arm B). Randomisation was stratified by hormone receptor status. Centrally reviewed FDG-PET was performed with pre-randomisation and after two treatment cycles. Arm A patients completed six cycles regardless of FDG-PET results. Arm B/FDG-PET–responders continued HP±endocrine therapy for six cycles; arm B/FDG-PET–nonresponders switched to six cycles of TCHP. Co-primary endpoints were the percentage of arm B/FDG-PET–responders with pathologic complete response (pCR) in the breast and axilla (ypT0/is ypN0) and 3-year invasive disease-free survival (iDFS) of arm B patients. Findings: Between 26 June 2017 and 24 April 2019, 356 patients were randomly assigned to arm A (n=71) or arm B (n=285). pCR occurred in 41 patients in arm A (57.7%, 95% Confidence Interval (CI) 47.4–69.4%) and 101 in arm B (35.4%, 95% CI 29.9–41.3%). Among arm B patients, 227 (79.6%) were FDG-PET–responders, 86 (37.9%, 95% CI 31.6–44.5%) of whom obtained pCR. No new safety signals were identified. Global health status declined ≥10% in 65.0% and 35.5% of patients in arms A and B, respectively. Interpretation: FDG-PET identified HER2-positive EBC patients likely to benefit from chemotherapy-free dual HER2 blockade with HP and a reduced impact on global health status. Depending on iDFS results, this strategy could select patients not requiring chemotherapy. Trial Registration: This trial is registered with EudraCT (‎2016-002676-27) and ClinicalTrials.gov (NCT03161353). Funding Statement: The study was conceived and designed by Medica Scientia Innovation Research (MEDSIR) in collaboration with F. Hoffmann-La Roche Ltd, which funded the study and provided the study drugs. MEDSIR, as legal sponsor of the study, is responsible for compliance with all clinical and regulatory procedures and adherence to the study protocol. Declaration of Interests: JMP-G reports to have a consulting role for Roche and Lilly, and travel expenses from Roche. GG reports research funding to the Institution from Roche and that an immediate family member received personal fees from Roche outside the submitted work. MRB reports to have a consulting role for Novartis, Pfizer, MSD, and to be part of speaker bureau for Pfizer, Novartis, Roche, Lilly, Astrazeneca. AS reports to have a consulting role for Roche and EISAI, to be part of speaker bureau for Roche and EISAI, expert testimony for ESIAI and Roche, and travel expenses from Roche and Pfizer. BB reports to have a consulting role for Genentech and MSD, to be part of speaker bureau for Genentech, and travel expenses from Pfizer. SE-de-R reports to have a consulting role for Roche, Pierre-Fabre, Eisai, research funding from Synthon and Roche, and travel expenses from Roche, Pierre-Fabre, and Daiichi Sankyo. AP reports honoraria from Pfizer, Novartis, Roche, MSD Oncology, Lilly, Daiichi Sankyo, Amgen, to have a consulting role for Amgen, Roche, Novartis, Pfizer, Brystol-Myers Squibb, Boehringer, PUMA Biotechnology, Oncolytics Biotech, Daiichi Sankyo, Abbvie, NanoString Technologies, research funding to the Institution from Roche, Novartis, Incyte, PUMA Biotechnology, to have intellectual property (PCT/EP2016/080056: HER2 AS A PREDICTOR OF RESPONSE TO DUAL HER2 BLOCKADE IN THE ABSENCE OF CYTOTOXIC THERAPY; WO/2018/096191. Chemoendocrine score (CES) Based on PAM50 for breast cancer with positive hormone receptors with an intermediate risk of recurrence), travel expenses from Daiichi Sankyo, other relationship with Oncolytics, Peptomyc S.L., and that an immediate family member is an employee of Novartis. MC reports to have a consulting role for Pierre-Fabre, Pfizer, OBI Pharma, Celldex, AstraZeneca, and honoraria from Novartis. NA reports to have a consulting role for Pfizer, Novartis, Roche, AstraZeneca, and Lilly, and travel expenses from Pfizer, Novartis, Roche, and AstraZeneca. MS-C reports honoraria from MEDSIR, Syntax for Science, and Nestle, to have a consulting role for MEDSIR, Syntax for Science, and Nestle, to be part of speaker bureau for MEDSIR, Syntax for Science, Roche, research funding from MEDSIR, Syntax for Science, and Roche, and travel expenses from MEDSIR, Syntax for Science, and Roche. AM is a full-time employee of MEDSIR. JC reports to have a consulting role for Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck Sharp&Dohme, GSK, Leuko, Bioasis, and Clovis Oncology, honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, and Daiichi Sankyo, research funding to the Institution from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, and Queen Mary University of London, and intellectual property for MEDSIR. AL-C reports leadership for Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, and MSD, intellectual property for MEDSIR and Initia-Research, to have a consulting role for Lilly, Roche, Pfizer, Novartis, Pierre-Fabre, GenomicHealth, and GSK, to be part of speaker bureau for Lilly, AstraZeneca, and MSD, research funding from Roche, Foundation Medicine, and Pierre-Fabre, Agendia, and travel expenses from Roche, Lilly, Novartis, Pfizer, and AstraZeneca. LC, NR, NM, CA, FD, and KK have nothing to declare. Ethics Approval Statement: This study was performed in accordance with guidelines of the International Conference on 205 Harmonization and ethical principles outlined in the Declaration of Helsinki. Written informed 206 consent was obtained before enrolment, and all participants agreed to study-specific procedures. 207 Approvals from appropriate regulatory authorities and ethics committees were obtained.

Background Eribulin 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. Methods An 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. Results Ninety-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. Conclusion In 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.

Background: Eribulin 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.Methods: An 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. Results: Ninety-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.Conclusions: In 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.

Background: HER2-positive breast cancer (BC) is a heterogeneous disease from a clinical and biological perspective. Intrinsic subtype defined by gene expression has an important role in determining response to treatment, as seen in several neoadjuvant trials (e.g. CALGB40601, CherLOB, NeoALTTO and PAMELA). However, limited data exist in an off-trial setting. The objective of this study was to evaluate the association of intrinsic subtypes with pathological completed response (pCR) and survival outcomes of a series of HER2-positive patients (pts) homogeneously treated with trastuzumab-based primary chemotherapy (PC) in a single comprehensive cancer center. Methods: Clinical-pathological data were evaluated in a series of 150 consecutive stage II-IIIC (T4d included) HER2-positive BC pts treated in ICO-Hospitalet (Spain) from August-2009 to December-2012 with weekly paclitaxel x12 followed by FEC/3w x 4 and concurrent trastuzumab for a total of 24w. HER2-positivity was considered according to ASCO-CAP 2007 guidelines. pCR was defined as ypT0/isypN0. The expression of 105 BC-related genes, including the PAM50 genes, was determined in baseline and residual formalin-fixed paraffin-embedded tumor samples using the nCounter platform. Intrinsic subtypes were determined by the research-based PAM50 gene expression predictor. Association of variables with pCR or disease-free survival (DFS) was evaluated using logistic regression analyses and cox proportional hazard models.All statistical tests were two-sided and considered significant when p≤0.05. Results: Most pts had T2 (64%) and T4 (20%) tumors and clinically node-positive disease (77%). 53% had hormonal receptor (HR)+ disease. 84 of the 150pts (56%) achieved a pCR; HR-neg was associated with higher pCR rates (72.5%vs 42% in HR+ P Conclusions: In this consecutive series of HER2-positive BCtreated homogeneously with neoadjuvant trastuzumab-based PC, all of the main intrinsic molecular subtypes were identified with a predominance of HER2-E. HER2-E was significantly associated with pCR and survival outcome. Distribution of the intrinsic subtypes in residual disease differed from untreated tumors. Citation Format: Pernas S, Petit A, Climent F, Pare L, Perez-Martin J, Ventura L, Galvan P, Falo C, Morilla I, Fernandez-Ortega A, Stradella A, Pascual T, Gil-Gil M, Prat A. PAM50 intrinsic subtyping as a predictor of pathological complete response to neoadjuvant trastuzumab-based chemotherapy in early HER2-positive breast cancer [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 P2-09-11.

Background: Palbociclib (PAL) is an oral cyclin-dependent kinase (CDK) 4/6 inhibitor that is under investigation in multiple oncologic clinical trials and is currently approved for use in combination with aromatase inhibitors (AIs) or fulvestrant (FUL) in patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2–) advanced breast cancer (BC). The PEARL Study is an ongoing international, open label, controlled, randomized Phase 3 study comparing the efficacy and safety of PAL in combination with endocrine therapy (exemestane [EXE] or FUL) versus capecitabine in postmenopausal women with HR+/ HER2– metastatic BC whose disease progressed on AIs. A secondary objective of the study was to evaluate the pharmacokinetics (PK) of PAL (125mg QD, 3 weeks on/1 week off) and EXE (25mg QD, continuously) when coadministered. This is the first study to investigate the drug-drug interaction (DDI) potential of the combination of PAL and the AI EXE. Methods: Patients (pts) randomized to the PAL+EXE arm of the PEARL Study in seven selected sites had the option of participating in the PK sub-study. Those who enrolled in the PK sub-study received EXE alone in a 7-day lead-in period immediately prior to Cycle 1 Day 1, when both drugs were coadministered on their standard dosing regimens. Sub-study pts were to have 2 pre-dose plasma PK samples drawn at steady-state (ss) during the lead-in period ("EXE Alone") for EXE determination, and 2 ss PK samples drawn for EXE and PAL determination (2 per analyte) during coadministration ("PAL+EXE"). Plasma concentrations of PAL and EXE were measured using validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. The withinpatient mean concentration of the PK samples which met ss acceptance criteria (WPM-Ctrough) for each analyte were generated for each treatment period as the input for DDI analyses. To assess the effect of coadministration of PAL on EXE PK, the WPM-Ctrough of EXE was compared within patients between the "PAL+EXE" (Test) and "EXE Alone" (Reference) treatment periods using a one-way analysis of variance (ANOVA) model with treatment as a fixed effect and patient as a random effect. To assess the effect of coadministration of EXE on PAL PK, the WPM-Ctrough of PAL was compared between the "PAL+EXE" period (Test) and historical data (Reference) using an ANOVA model. Analysis of covariance (ANCOVA) models were used to assess the impact of demographic differences between analysis populations in covariates known to impact PAL PK on the ANOVA model conclusions. Results: A total of 26 pts randomized to the PAL+EXE arm were enrolled in the PK sub-study and had PK samples analysed, of which 23 meet ss acceptance criteria. The ratio of the adjusted geometric means for EXE WPM-Ctrough was 106.9% (90%CI: 82.4-138.8), when EXE was administered with PAL, compared with its administration alone. Likewise, the models to assess potential for EXE to perpetrate DDI on PAL PK showed ratios of adjusted geometric means of 102.4% (90%CI: 82.0-127.9) and 111.6% (90%CI: 90.3137.8), when adjusted for covariates. Conclusion: The PK data indicate a lack of a clinically meaningful DDI between PAL and EXE when the 2 drugs are coadministered. Sponsor: GEICAM Citation Format: Martín M, Hoffman J, Ruiz-Borrego M, Muñoz M, Calvo L, Crownover P, García-Sáenz JA, Alba E, Wang D, Thallinger C, Stradella A, Montaño Á, Adamo B, Antolín S, Moreno-Antón F, Falo C, Ruiz V, Martín N, Caballero R, Carrasco E, Gil-Gil M. Evaluation of the drug interaction potential of palbociclib and exemestane – Results from the PEARL pharmacokinetic sub-Study [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 P5-21-23.

1057 Background: Cyclin-dependent kinase (CDK) 4 & 6 inhibitors plus endocrine therapy (ET) are standard of care for advanced HR+ BC. Combining xentuzumab, an insulin-like growth factor (IGF) ligand-neutralizing antibody, with ET and everolimus, suggested progression-free survival (PFS) benefit in pts with advanced HR+ BC and non-visceral disease. Activation of the IGF pathway leads to an increase in cyclin D1, providing a rationale for combining IGF and CDK4 & 6 inhibition. This prospective, open-label study is investigating xentuzumab plus abemaciclib, a CDK4 & 6 inhibitor, with fulvestrant. In dose-finding cohorts, the recommended phase II dose (RP2D) was determined as xentuzumab 1000 mg weekly intravenously plus abemaciclib 150 mg every 12h orally (Q12h). Here, we report preliminary data on disease control rate (DCR) from two expansion cohorts in pts with advanced HR+ BC with visceral (D1) or non-visceral disease (D2). Methods: Postmenopausal women with advanced/metastatic HR+ BC that had progressed on or after ET (including adjuvant ET) were enrolled. Pts could not have received >1 line of ET or any chemotherapy for metastatic disease. No prior CDK4 & 6 inhibitor therapy was permitted. Pts had to have ≥1 documented visceral metastasis in D1 and no visceral metastases in D2. Pts received xentuzumab weekly plus abemaciclib Q12h (at RP2D) plus fulvestrant 500 mg per label. Protocol primary endpoint was PFS rate at 18 months (mos). Secondary endpoints included DCR (complete response [CR], partial response [PR] and non-CR/non-progressive disease [PD] or stable disease [SD] lasting ≥24 weeks [wks]). Results: In D1/D2, 33/31 pts were treated: median age 60/53 years. 19 pts in D2 had bone-only, non-measurable disease. At data cut-off (Jan 2021), median treatment duration was 7.5/9.2 mos in D1/D2; 40 pts remain on treatment. In D1, DCR was 64%: 17 (52%) pts had PR and 4 (12%) had SD lasting ≥24 wks. In D2, DCR was 55%: 5 (16%) pts had PR, 10 (32%) had non-CR/non-PD lasting ≥24 wks and 2 (7%) had SD lasting ≥24 wks. Median duration of disease control was 10.9 mos in each cohort. Some pts had not reached 24 wks; full DCR data will be presented. Most common AEs are shown in the table (≥33% all-grade in either cohort). No hypo/hyperglycemia was reported. Conclusions: Xentuzumab plus abemaciclib and fulvestrant demonstrated encouraging disease control in pts with advanced HR+ BC with visceral and non-visceral disease. The safety profile was manageable, and consistent with the known profiles of the three agents. Clinical trial information: NCT03099174 .[Table: see text]

Introduction: The addition of Trastuzumab(T) to chemotherapy (CT) revolutionized HER2-positive breast cancer(BC) and changed its natural history. We reviewed the efficacy of T outside clinical trials in a cancer comprehensive center. Methods: Ambiespective and descriptive study was conducted in Catalan Institute of Oncology (ICO-Barcelona). Estimates of progression-free survival (PFS) and overall survival (OS) were obtained with the Kaplan-Meier method and compared with LogRank test. The association of clinic-pathological variables and outcome was studied by χ2and Cox proportional hazard analysis. Results: 430 consecutive early HER2-positive BC patients (pts) were treated with adjuvant/neoadjuvant T and CT from Jan 2005 to Dec 2012. Pt basal characteristics are reported in Table 1. Neoadjuvant treatment was administrated in 230pts (54%) and in 200 (46%) in adjuvancy. Pathological complete response (pCR) in breast and nodes (ypT0/isypN0) was achieved in 48% of pts, with higher rates in hormone receptor (HR)-negative pts (62 vs 37% p=0.0005). Median duration of T: 10.6 months (m). 28%pts treated with neoadjuvant T+CT who achieved a pCR did not receive adjuvant T. Treatment discontinuation: 38pts (8.8%): 27pts due to cardiac toxicity and 4 relapsed during adjuvant T. In 87%pts, neoadjuvant CT was based on anthracyclines(A) and taxanes. Adjuvant CT: A and taxanes in 57.4%; 14%pts FAC, 15.4% A-CMF and 12% TCH. At a median follow-up of 70m (3-135), 44pts (10.4%) had relapsed: 33pts with distant M1, 9pts with only loco-regional disease and 2pts contralateral HER2-positive BC. M1 location: 46% visceral, 34% bone/lymph nodes and 20% in central nervous system (CNS). PFS was 23.4m(0-88); median OS was not reached; estimated 10 years-OS was 86.5%. Pts treated with A and taxanes had a significantly better OS compared to those treated with other CT (113 vs 98m, p= 0.009). Kaplan-Meier curve showed numerically higher relapses at 10 years in HR-positive pts (83 vs 90% p=0.8). Pts with pCR had significantly better OS (113 vs 104m, p=0.006). Pts with CNS-metastases had a significantly worse OS (13 vs 26m,p=0,02) and those with HR-negative (49 vs 24m, p= 0.033). Conclusion: In everyday clinical practice, recurrences after adjuvant/neoadjuvant trastuzumab in HER2-positive BC were less than described in the T-pivotals trials, with 10% of recurrences at a median of FU of 70m. In our series, estimated 10 years-OS was 86.5%. Pts treated with A and taxanes had a significantly better OS as well as those pts who achieved a pCR. On the contrary, pts with CNS M1 and those with HR-negative had worse prognosis. Table 1Median age51.9y (27-83)Stage I/II/III106 (25%)/ 226 (52%)/ 97 (23%)HR Positive/ Negative249 (58%)/181 (42%) Citation Format: Ortega A, Domenech M, Falo C, Gil M, Stradella A, Fernandez A, Morilla I, Villanueva R, Castany R, Vazquez S, Molina K, Bergamino M, Navarro V, Pernas S. Treatment of early HER2-positive breast cancer in trastuzumab era in everyday clinical practice: An overview after 10 years of its approval [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-32.

Introduction: HER2-enriched subtype has been associated with a higher response to neoadjuvant anti-HER2-based therapy across various clinical trials. However, limited data exist in real-world practice and regarding residual disease. Here, we evaluate the association of HER2-enriched with pathological response (pCR) and gene expression changes in pre- and post-treatment paired samples from patients with HER2-positive breast cancer treated outside of a clinical trial. Methods: We evaluated clinical-pathological data from a consecutive series of 150 patients with stage II-IIIC HER2-positive breast cancer treated from August 2004 to December 2012 with trastuzumab-based neoadjuvant chemotherapy. Expression of 105 breast cancer-related genes, including the PAM50 genes, was determined in available pre-and post-treatment formalin-fixed paraffin-embedded tumor samples using the nCounter platform. Intrinsic molecular subtypes were determined using the research-based PAM50 predictor. Association of genomic variables with total pCR was performed. Results: The pCR rate was 53.3%, with higher pCR among hormonal receptor (HR)-negative tumors (70% vs 39%; P

Pathogenic sequence variants (PSV) in

Homocisteïna; Càncer de mama; Dieta cetogènica Homocisteína; Cáncer de mama; Dieta cetogénica Homocysteine; Breast cancer; Ketogenic diet Certain dietary interventions might improve the therapeutic index of cancer treatments. An alternative to the “drug plus diet” approach is the pharmacological reproduction of the metabolic traits of such diets. Here we explored the impact of adding metformin to an established therapeutic regimen on the systemic host metabolism of cancer patients. A panel of 11 serum metabolites including markers of mitochondrial function and intermediates/products of folate-dependent one-carbon metabolism were measured in paired baseline and post-treatment sera obtained from HER2-positive breast cancer patients randomized to receive either metformin combined with neoadjuvant chemotherapy and trastuzumab or an equivalent regimen without metformin. Metabolite profiles revealed a significant increase of the ketone body β-hydroxybutyrate and of the TCA intermediate α-ketoglutarate in the metformin-containing arm. A significant relationship was found between the follow-up levels of homocysteine and the ability of treatment arms to achieve a pathological complete response (pCR). In the metformin-containing arm, patients with significant elevations of homocysteine tended to have a higher probability of pCR. The addition of metformin to an established anti-cancer therapeutic regimen causes a fasting-mimicking modification of systemic host metabolism. Circulating homocysteine could be explored as a clinical pharmacodynamic biomarker linking the antifolate-like activity of metformin and biological tumor response. This work was supported by grants from the Ministerio de Sanidad, Servicios Sociales e Igualdad (EC10-125, Ayudas para el Fomento de la Investigación Clínica Independiente to Begoña Martin-Castillo). Work in the Menendez laboratory is supported by the Ministerio de Ciencia e Innovación (Grant SAF2016-80639-P, Plan Nacional de l+D+I, founded by the European Regional Development Fund [EU FEDER], Spain) and by an unrestricted research grant from the Fundació Oncolliga Girona (Lliga catalana d’ajuda al malalt de càncer, Girona).