Pretreated Metastatic Breast Cancer Patients Research Articles

A genetically engineered epothilone analog as a novel oral microtubule inhibitor: A clinical study of utidelone capsule for advanced breast cancer.

e13115 Background: Utidelone, a genetically engineered epothilone analog, is a potential best-in-class novel microtubule stabilizing agent. Utidelone injection was approved for advanced breast cancer in China in 2021. Utidelone is not susceptible to P-glycoprotein, leading to better oral bioavailability and successful development of an oral formulation-Utidelone Capsule (UTD2). As of now, there has been no oral microtubule stabilizing agent approved in China and the United States. UTD2 may benefit patients in various aspects including effectiveness, safety, better compliance, reduced medical cost, and facilitation of combination therapy, especially with other oral anti-cancer drugs. This is the first clinical study in China to investigate the efficacy and safety of UTD2 monotherapy for treatment of advanced breast cancer. Methods: This is an ongoing open-label, multi-center study (NCT05700084) consisting of three parts: dose escalation, bioavailability and food effect, and in combination with capecitabine for treatment of metastatic breast cancer. Here we report the preliminary results from single center for part I with determination of DLT and MTD as the primary objective, and efficacy, PK profile and safety in patients with pretreated metastatic breast cancer as the secondary objectives. Eligible patients are aged 18-70 years with confirmed advanced breast cancer refractory to prior standard therapies, and have an ECOG PS of 0-1, life expectancy ≥12weeks. Patients are treated with UTD2 monotherapy, at starting dose of 50 mg/m2/d-5day for two patients, with planned escalation (3+3) to 75 mg/m2/d-5day and 75 mg/m2/d-7day, then to 85 mg/m2/d-7day or down to 70 mg/m2/d-7day in a 21-day cycle. Results: As of 25th January 2024, 5 advanced breast cancer patients were enrolled, who had received prior treatment in advanced settings. Dose escalation is ongoing, and 75mg/m2/d-7day cohort is under evaluation. Four patients were evaluated for efficacy with an outcome of 2 PR (each for 50 and 75mg/m2/d-5day dose) and 2 SD (75mg/m2/d-5day dose) with treatment durations of 2 to 8 cycles. Most treatment-emergent adverse events (TEAEs) were Grade 1/2, manageable, and included peripheral sensory neuropathy (PN), dizziness and loss of appetite. There were two patients encountered Grade 3 TEAEs including one with PN and one with diarrhea/insomnia, that recovered through dose reduction or supportive treatment. No grade 4/5 adverse events and no treatment discontinuations due to AE were reported. There have been no DLTs and the MTD is not yet reached. Conclusions: These preliminary results suggested promising efficacy with a manageable safety profile of UTD2 in pretreated metastatic breast cancer patients. This study is still actively enrolling; further data will be provided at the time of presentation. Clinical trial information: NCT05700084 .

Comparative survival analysis of patients with HER2-low and HER2-positive metastatic breast cancer with or without brain metastases treated with trastuzumab deruxtecan.

1036 Background: Breast cancer outcomes vary among HER2-amplified and HER2 low-expression patients, particularly in the presence of brain metastases (BM). Trastuzumab deruxtecan (T-DXd) is FDA approved for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-low and HER2-positive (HER2+) patients (pts). This study aims to evaluate the impact of T-DXd treatment on overall survival among HER2 low and HER2-positive metastatic breast cancer (MBC) patients with and without brain metastases (BM). Methods: A retrospective analysis was conducted by using de-identified data available from seven US-based health systems part of Guardian Research Network (GRN). Patients treated with T-DXd from December 2019 to December 2023 with a diagnosis of HER2 low (immunohistochemistry [IHC] 1 + or IHC 2+/negative with HER2 FISH non-amplified) and HER2+ (IHC 3+ or HER2+ and FISH amplified MBC were included. Median overall survival (mOS), calculated from the initiation of T-DXd treatment, was assessed using Kaplan-Meier Curve analysis and Log-rank test. Results: A total of 380 MBC pts were identified. Among these 231 (61.1%) were stratified as having HER2 low and 149 (38.9%) HER2+ MBC. Pts with HER2+ disease had a higher prevalence of BM (n=70; 47%) compared to HER2-low pts (n=55;23.8%). The median age at BM diagnosis was 60.5 years, range: 21.6 to 87.1 years. Within the entire BM group (n=125), there were more pts with ER+ disease (81.9%) in the HER2 low group compared to HER2+ group (55.8%, p=0.01). The majority of these patients had multiple prior lines of therapy. HER2+ BM pts had a median overall survival (mOS) of 9.3 months [CI: 6.79-11.88, log rank p <0.001], compared to 4.3 months [CI: 1.89-6.82, log rank p <0.001] in the HER2-low pts. Without BM, HER2+ pts had a mOS of 10.7 months [CI: 0.71-20.82, log rank p <0.001], compared to 6 months [CI: 3.47-8.67, log rank p <0.001] in the HER2-low pts. Conclusions: In this retrospective study of heavily pretreated MBC patients with multiple prior lines of therapy, pts with HER2+ MBC with and without BM had a longer mOS compared to those with HER2- low disease, suggesting HER2 expression as a key determinant of T-DXd efficacy. Poor survival in MBC patients without BM was attributed to pre-treatment with multiple lines of therapy. Future research should explore combination therapies and predictive biomarkers while conducting clinical trials to optimize treatment strategies for HER2+ metastatic breast cancer patients.

A pilot study of the combination of entinostat with capecitabine in high-risk breast cancer after neoadjuvant therapy.

e13107 Background: Breast cancer has an unacceptably high recurrence rate when residual disease is found following neo-adjuvant treatment of high-risk disease. Based on clinical data suggesting an adjuvant role for epigenetic modifying agents in breast cancer and preclinical data suggesting synergistic activity of entinostat combined with capecitabine, we conducted a phase I, open label study of these agents in metastatic breast cancer (MBC). Both agents have published doses for use in combination therapy, but the agents had not previously been combined with each other in a human trial. Methods: A multisite phase I dose escalation study was performed at two academic centers. Patients with pretreated, HER2 negative MBC, and measurable disease were enrolled. Dual dose escalation was performed via a Bayesian partial order continual assessment method. Dose levels ranged from entinostat 3mg to 5mg and capecitabine 800mg/m2 to 1000mg/m2. Results: Thirteen patients with MBC and a median of 4 lines of prior therapy were enrolled across four dose level combinations. The most common toxicities were neutropenia, thrombocytopenia, and palmar- plantar erythrodysesthesia, which were expected toxicities. No new safety signals were observed. One dose-limiting toxicity was observed, which did not exceed a pre-specified toxicity rate of 25%. The median treatment duration was 2.37 months. No partial nor complete responses were observed. The study was halted early prior to entering an expansion phase. Conclusions: The tested dosing combinations of entinostat and capecitabine are likely safe in heavily pretreated metastatic breast cancer patients. Entinostat clinical investigation in breast cancer was halted while this study was ongoing. Clinical trial information: NCT03473639 .

A nationwide observational study in heavily pretreated metastatic HER2-positive breast cancer patients

Background Current guidelines in HER2-positive metastatic breast cancer (mBC) recommend the combination of trastuzumab and a chemotherapeutic agent for 3rd line or later treatments. This study aims to describe the treatment of HER2-positive mBC in 3rd line or later after previous treatment with T-DM1 for mBC in a real-world setting. Material and methods This observational population-based study included all women diagnosed with HER2-positive mBC in Denmark, previously treated with T-DM1 in the metastatic setting. Patients were included on the date of progression leading to initiation of 3rd line treatment if the patient had received T-DM1 in 1st or 2nd line. If the patient received T-DM1 in 3rd line or later the inclusion was based on the date of progression on T-DM1. The primary end points were overall survival (OS) and progression-free survival (PFS). Results The study included 272 women with a mean age of 59 (27–86) and a median of 3 (2–11) treatment lines prior to inclusion. At index, all patients had received T-DM1 and 167 (62%) patients had received pertuzumab in the metastatic setting. During follow-up 183 patients received chemotherapy. Of these patients, 120 received chemotherapy combined with trastuzumab, 50 received chemotherapy combined with other HER2-targeted therapy, and 13 received chemotherapy as monotherapy. The remaining 89 patients received either HER2-targeted monotherapy (41), endocrine therapy (31), experimental treatment (10), or no treatment (7). Median PFS was 5.5 months (95% CI, 4.8–6.5) and median OS was 18.5 months (95% CI, 16.2–21.3). Conclusion In this real-world study, we found that patients were treated with a wide variety of anti-cancer agents with modest efficacy. However, patients in this study did not have access to newer therapies like tucatinib and T-DXd.

Efficacy and safety of margetuximab plus chemotherapy vs. trastuzumab plus chemotherapy in Chinese patients with pretreated HER2-positive advanced metastatic breast cancer: results from a randomized, open-label, multicenter, phase II bridging study.

Trastuzumab is the recommended first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) patients in China, but therapeutic resistance to trastuzumab and other early-line treatments is common and late-line treatment options are limited. Derived from the same murine precursor antibody, margetuximab has enhanced anti-tumor activity compared with trastuzumab and may be an effective late-line treatment. However, data regarding the use of margetuximab in pre-treated Chinese patients are scarce. This study aimed to evaluate the efficacy and safety of margetuximab plus chemotherapy vs. trastuzumab plus chemotherapy in Chinese patients, and to determine whether the results are consistent with the clinical benefit of margetuximab observed in the pivotal global phase III study. In this randomized, open-label, multicenter, phase II bridging study, eligible Chinese patients pretreated with ≥2 lines of anti-HER2 therapies were randomized 1:1 by stratified block randomization to margetuximab (15 mg/kg over at least 120 minutes) or trastuzumab (6 mg/kg over at least 30 minutes), each administered intravenously once every 21-day cycle and plus chemotherapy. Disease assessment was conducted once every two treatment cycles (6 weeks ± 7 days). The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR). Secondary endpoints included overall survival (OS), investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR), and the incidence and severity of treatment-emergent adverse events (TEAEs). Between February 4, 2020 and February 23, 2021, 123 patients were randomized to the margetuximab (n=62) and trastuzumab (n=61) arms. Among them, 15 and 7 patients, respectively, were still on study treatment as of data cut-off (September 3, 2021). Overall, 99.2% were female, median age was 53 years old. All patients were pretreated with trastuzumab, and 83.7% and 25.2%, respectively, were pretreated with tyrosine kinase inhibitors (TKIs) and pertuzumab. Baseline characteristics were numerically balanced between arms. BICR-assessed median PFS (mPFS) was 5.5 months in the margetuximab arm and 4.1 months in the trastuzumab arm, with a hazard ratio (HR) of 0.69 [95% confidence interval (CI): 0.43-1.12], which met the consistency criterion (HR <0.88) for bridging success. Median investigator-assessed PFS was 5.5 months in the margetuximab arm and 4.0 months in the trastuzumab arm (HR =0.63; 95% CI: 0.41-0.96). Median OS (mOS) was not yet reached. Both ORR and CBR were greater in the margetuximab arm (25.5% vs. 12.5%; 32.7% vs. 14.3%). Safety results were numerically comparable between the two arms. Anti-HER2 treatment-related infusion-related reactions (IRRs) were more common in the margetuximab arm than in the trastuzumab arm (12.9% vs. 1.7%). All IRRs could be resolved. Margetuximab was effective and well-tolerated in this study, supporting its clinical use in pretreated HER2-positive MBC patients in China. ClinicalTrials.gov Identifier: NCT04262804.

247P Apatinib combined with chemotherapy versus single chemotherapy in advanced HER-2-negative breast cancer: A randomized, controlled, open-label phase II study

Apatinib is an oral, highly potent tyrosine-kinase inhibitor targeting VEGFR2. Phase II trial of apatinib in triple-negative breast cancer that have failed at least three chemotherapy regimens have demonstrated apatinib dose of 500 mg rather than 750 mg is the recommended starting dose for the heavily pretreated metastatic triple-negative breast cancer (mTNBC) patients with measurable rate of partial response and PFS. This phase II trial aimed to investigate the efficacy and safety of apatinib combined with chemotherapy in patients with HER2-negative advanced breast cancer.

Tumor mutational burden in non-immunotherapy patients with heavily pretreated metastatic breast cancer: long-term outcomes from a single institution

Patients with heavily pretreated (≥3rd-line treatment) metastatic breast cancer (MBC) had poor outcomes and lack prognostic biomarkers. Tumor mutational burden (TMB) was a prognostic biomarker for immunotherapy, but is not well defined in non-immunotherapy. Forty-nine heavily pretreated MBC not received immunotherapy were enrolled between March 2016 and September 2018. TMB of metastatic tumor tissue was evaluated by targeted next-generation sequencing of a 247-genes panel. CBRs (clinical benefit rates) were 47.7% (9 months), 36.2% (12 months) in high TMB patients, higher than 16.1% (9 months), 8.1% (12 months) in low TMB patients, respectively. After a median follow-up of 38 months, patients with high TMB had a longer mPFS (median progress-free survival) compared to low TMB patients in 3rd-line treatment group (13.5 versus 7 months, HR 0.32, p = 0.019) but not in >3rd-line treatment group. Cox regression showed TMB and line of treatment were the two independent prognostic factors for prolonged mPFS in heavily pretreated MBC, with a HR of 0.34 (p = 0.009) for high TMB and 0.37 (p = 0.013) for 3rd-line treatment. In luminal subtype, mPFS was longer with endocrine therapy (ET) alone than with endocrine therapy + chemotherapy (ET + CT) in high TMB cohort (p = 0.037) but shorter mPFS with ET alone than with ET + CT in low TMB cohort (p = 0.047). High TMB and line of treatment are two independent prognostic factors for prolonged mPFS in heavily pretreated MBC patients. TMB may be a predictive biomarker of efficacy with ET alone or ET + CT in luminal subtype.

Prognostic and predictive factors of eribulin in patients with heavily pre-treated metastatic breast cancer.

A predictive marker for efficacy of eribulin administered as different lines of treatment in metastatic breast cancer (MBC) has not been identified. We aimed to determine the predictive factors for efficacy of eribulin administered as different lines of treatment in MBC patients.This restrospective cohort study included 49 heavily pre-treated MBC patients who received either eribulin monotherapy or combination therapy with eribulin and anti-Her2 therapy. Associations between clinical response of eribulin-based treatment, time-to-treatment failure (TTF), and possible predictive markers were investigated.Patients’ median age was 55 years; 65% were ER+; 43% were HER2+; and 16% were triple-negative. Median TTF was 5.23 months and longer in non-visceral metastases patients. Eastern Cooperative Oncology Group (ECOG) status was 0–1; eribulin as ≥2nd-line treatment; eribulin combined with dual blockades; lymphocyte-monocyte ratio (LMR) ≥3; and monocyte-lymphocyte ratio (MLR) <0.4. In patients with eribulin as >3rd-line treatment, univariate analysis showed that ECOG status was 0–1, and LMR ≥3 and MLR <0.4 were associated with a low risk of TTF. Multivariate analysis showed that ECOG status 0–1 was an independent protective factor. Leukopenia and neutropenia were the most common manageable adverse events.ECOG status is an independent predictor for TTF, while LMR and MLR may have an interactive effect with other biomarkers (e.g., ECOG status) to predict response in MBC patients receiving eribulin as ≥2nd-line treatment.

Prospective Evaluation of a Circulating Tumor Cell Sensitivity Profile to Predict Response to Cisplatin Chemotherapy in Metastatic Breast Cancer Patients.

BackgroundCisplatin (cDDP) has regained interest for metastatic breast cancer (MBC) patients, given the platinum sensitivity in subtypes and better manageable toxicity. Here, the primary aim was to determine whether molecular characteristics of circulating tumor cells (CTCs) could identify patients responding to cDDP and to describe the outcomes to cDDP monotherapy in a large group of MBC patients pretreated with anthracycline- and taxane-based treatments.MethodsBased on cell line data, a CTC-cDDP-sensitivity profile was generated. Applying an A’Herns single-stage phase II design, further investigation was considered worthwhile if 5/10 patients with a favorable profile responded to cDDP. Patients received 70mg/m2 cDDP every three weeks, CTCs were enumerated and the CTC-cDDP-sensitivity profile was determined. In total, 65 heavily pretreated MBC patients (77% received ≥2 lines of previous chemotherapy for MBC) were eligible for the per-protocol analysis. Primary endpoint was response rate, secondary endpoints included best observed response, progression-free survival (PFS) and overall survival (OS).ResultsThe best observed response during cDDP therapy was a partial response in 7% and stable disease in 56% of the patients. None of the patients with a favorable CTC-cDDP-sensitivity profile had a response. The median baseline CTC count was 8 (range 0-3254). Patients with <5 CTCs had a better PFS and OS than patients with ≥5 CTCs (median PFS 4.5 months (95%CI 2.38-6.62) vs. 2.1 months [(95%CI 1.34-2.80)(p=0.009)] and median OS 13.1 months (95%CI 9.89-16.33) vs. 5.6 months [(95%CI 3.60-7.64)(p=0.003)]. No other factors than CTC count were associated with outcome to cDDP therapy, including triple-negative breast cancer versus ER-positive tumors.ConclusionsThe CTC-cDDP-sensitivity profile was unable to select patients responding to cDDP monotherapy. In an unselected group of heavily pretreated MBC patients, cDDP yields outcomes comparable to other chemotherapeutic regimens for heavily pretreated MBC patients. CTC count was the only factor associated with outcome in these patients.Clinical Trial Registration(https://www.trialregister.nl/trial/3885, identifier NTR4046)

Abstract PD1-07: A Phase 2 study of poziotinib in patients with HER2-positive metastatic breast cancer heavily pre-treated with HER2-targeted therapy

Abstract Background: Poziotinib is a novel pan-HER inhibitor that irreversibly blocks the EGFR family of tyrosine-kinase receptors and inhibits the proliferation of tumor cells. This study evaluates the safety and clinical activity of poziotinib in patients with HER2-positive metastatic breast cancer (MBC) who received at least 2 therapies (trastuzumab and TDM-1) in dose-schedule ranging study. Methods: Patients were treated with oral poziotinib in 2 dose cohorts: 24mg daily 2 weeks/1 week off and 16mg daily continuously in a 21-day cycle. Dose reduction was allowed if toxicity observed. Patients continued treatment until disease progression, death, intolerable AE, or for a maximum of 24 months. The primary endpoint was the objective response rate (ORR), evaluated using RECIST 1.1. Secondary endpoints included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS) and safety. Results: Sixty-seven patients (33 in 24mg; 34 in 16mg) were enrolled (57 evaluable) in 2 cohorts; all patients either completed or discontinued (36 PD, 5 deaths due to PD, 16 AEs) the study with 1 completed 25 months of treatment. The median (range) age was 57 (29-94) years. Patients were heavily pretreated and the median (range) lines of previous therapy were 7 (2-13) and 4 (2-16) in 2 cohorts respectively [unique drugs 3 (2-5) and 3 (1-9)]; 75% received pertuzumab in addition to trastuzumab and TDM-1 and 37% received at least one tyrosine kinase inhibitor (TKI). The mean relative dose intensity was 57% and 51% with 67% and 47% had dose reductions in 2 cohorts respectively. Common Grade ≥3 treatment-related AEs were similar to other 2nd generation TKIs and include diarrhea (30%), rash (28%) and stomatitis (7%). The ORRs were 27% and 26% with the corresponding median DORs of 5.6 and 13 months respectively. 3 patients in 16mg dose had a CR and another 2 patients had an unconfirmed CR. The DCRs were 50% and 70% in 2 cohorts along with median PFS of 4.1 and 5.8 months respectively. The ORRs were 25% each in 2 cohorts in 24 and 20 heavily pre-treated patients with ≥4 lines of therapy that included trastuzumab, TDM1 and pertuzumab. The ORRs were 23% and 0% in 2 cohorts with 13 and 10 patients received at least one tyrosine kinase inhibitor (TKI) as the sample sizes were small to make any meaningful evaluation. Conclusion: Poziotinib has demonstrated clinical activity in this dose-ranging study with tumor reduction shown in the majority of patients along with durable responses in this heavily pre-treated MBC patients. Safety profile was mechanism related and was similar to other 2nd generation TKIs. Citation Format: Adam Brufsky, Malik Zulfiqar, Julio Peguero, Kate Lathrop, Gajanan Bhat, Francois Lebel. A Phase 2 study of poziotinib in patients with HER2-positive metastatic breast cancer heavily pre-treated with HER2-targeted therapy [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 PD1-07.

263 Poster - Real-World data of triplet combination of trastuzumab, lapatinib and chemotherapy in HER2-positive metastatic breast cancer: A multicenter retrospective study

Background: Trastuzumab(T) plus lapatinib(L) has been demonstrated to significantly improve the outcome of HER2 positive heavily pretreated metastatic breast cancer (MBC) patients. Whether TL combined chemotherapy (TLC) can further improve the efficacy in HER2+ MBC remains to be further studied. The aim of this study was to assess real-world treatment patterns and clinical outcomes of patients treated with TLC.

Abstract P1-16-03: Hear our voice: Patient-driven solutions to increase participation in clinical trials

Abstract Background: The rate of participation in clinical trials is dismally low, slowing the process of drug development and increasing cost. Patients living with metastatic breast cancer (MBC) are often willing to participate in clinical trials, but are frequently faced with insurmountable barriers. There is a dire need for studies identifying actionable patient-driven solutions to help ensure that opportunities to participate in clinical trials becomes more equitable, attractive and feasible for a larger, more diverse pool of potential participants. Methods: A mixed-methods design including in-depth interviews and online surveys was used to identify barriers and solutions to participation in clinical trials. Sixty-one participants were invited to be interviewed using purposeful stratified sampling (patient race, age and geographic location; community and academic center oncologists and administrators; researchers and research staff; payers). Interview questions were designed to collect feasible solutions to barriers. Convenience sampling was used to recruit MBC patient survey participants. Online surveys were fielded via nine MBC social media groups reaching approximately 1,500 patients living with MBC. Survey questions included demographics, trial experience, perception of benefits/disadvantages and barriers to trial participation, and ideas for solutions to the barriers. In addition, a short social media poll on trial participation was used. Results: A total of 496 women living with MBC completed the online survey. The mean age of survey respondents was 53 years old and mean number of years with MBC was 4.6 years. Respondents generally reported positive attitudes toward trial participation: The opportunity to get innovative treatments, helping others with MBC and contributing to research were rated as extremely important. Potential disadvantages included fear of side effects, possibility that trial drugs may not be effective and financial toxicity. Significant barriers included strict eligibility criteria, broad exclusion criteria and lack of trials nearby. All patients responding to a social media poll indicated they would consider participating in a clinical trial. Fifty-two participants were interviewed. The most frequent themes from patients were suggestions to address rigid eligibility and exclusion criteria by consistently including patients in research design, protocol development and policy decisions. Patients felt that trials should reflect the “real world”, and that opening up eligibility criteria would increase diversity and the number of potential participants. A dominant theme from rural and community-based oncologists was the need to address geographic, logistical and financial barriers using more “portable” multi-institution trials, providing transportation and adequate reimbursement for patients’ expenses. Clinicians in academic described exclusion criteria as a significant barrier for heavily pretreated MBC patients. Health care administrators discussed solutions to high costs associated with trials. Payers shared innovative solutions to out-of-network payment barriers. Conclusions: Most patients with MBC are willing to participate in clinical trials, and many are highly motivated to do so. MBC patients generally recognize the benefits that trials can offer and are willing and able to help address the barriers to trial participation by working collaboratively across the board. Multiple sectors of health-care are ready and willing to work together. It is in all our best interests to hasten the development of new treatments, and the time is right to implement a collaborative, systematic solutions-based approach that will make it feasible for more MBC patients to participate in clinical trials. This patient led study shows how this can be done. Citation Format: Marina Kaplan. Hear our voice: Patient-driven solutions to increase participation in clinical trials [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 P1-16-03.

Abstract P4-05-09: Molecular differences between high and low tumor mutational burden (TMB) across breast cancer (BC) subtypes

Abstract Background. High-TMB (HTMB) is an emerging promising agnostic biomarker for predicting benefit from immune-checkpoint inhibitors, independently of tumor type. At ASCO 2019, the TAPUR trial reported an interesting 21% ORR in heavily pretreated metastatic BC patients with very HTMB [vHTMB, ≥9 mutations/megabase (Muts/Mb)]. We aimed to define the differential gene expression and methylation landscape between low and high TMB in each BC subtype. Methods. In TCGA, we identified 848 patients with WES data available for TMB estimation. [ER+/HER2- (LumA by PAM50)) n = 364; ER+/HER2- (LumB by PAM50), n = 147; HER2+, n = 158; and TN, n = 179]. High TMB was defined according to two different cut-offs: ≥9 (vHTMB) and≥5 Muts/Mb (HTMB). The second arbitrary cut-off was used to define a larger group allowing to better characterize the different molecular landscapes associated with high and low TMB in each BC subtype. The HTMB group was compared with an equal number of tumors with low TMB. We assessed the differential RNA expression and methylation of single genes and pathways (defined using Gene Ontology - GO). “Common” genes and pathways were defined as recurrently associated with TMB (p&amp;lt;0.05) in all subtypes and with a combined p value ≤0.00001. Results. The overall prevalence of vHTMB (≥9) was 4.5%, with no substantial differences across subtypes (4.4%, LumA; 4.8% LumB; 5.7% HER2+; 3.3% TN). The prevalence of HTMB (≥5) was 13.7%, but it was different across BC subtypes (p=8.0E-07) (8.2%, LumA; 12.9% LumB; 13.3% HER2+; 25.7% TN). We found more “common” genes down-regulated (n=70) than up-regulated (n=3) in HTMB group. Two of these three genes (HSPE1 and FEZF1.AS1) have been associated with poor prognosis in BC. When we considered the “common” pathways, only 3 were up-regulated in HTMB, all implicated in post-transcriptional repression of gene expression (gene silencing by miRNA and mRNA binding involved in post-transcriptional gene silencing). Conversely, 66 were significantly down-regulated (including transcription coregulator and coactivator activity, protein serine/threonine kinase activity and ubiquitin-protein transferase activity and binding). Some genes and pathways were associated with TMB only in a specific BC subtype (p ≤0.00001). For instance, 16 pathways were down-regulated in the HTMB group of TNBC. These inlcuded 12 pathways implicated in immune response. Conversely, in LumB, 11 pathways were up-regulated in HTMB group and implicated in immune response. Intrestingly, these pathways were all significantly down-regulated in the HTMB group of LumA and TN. In HTMB group, we found 7 and 4 “common” genes hypermetylated and hypomethylated, respectively. Four pathways were commonly hypermethylated (chromatin silencing at rDNA, telomere organization and positive regulation of G1/S transition of mitotic cell cycle) and five were hypomethilated (including mitotic sister chromatid segregation). Considering private alterations, in TNBC, 23 of 27 significant pathways were hypermetylated in HTMB group including double-strand break repair via nonhomologous end joining, epigenetic negative regulation of gene expression, and regulation of gene silencing by miRNA. Conclusions. Very-high TMB which is considered potentially druggable (≥9 Muts/Mb) is rare in BC, and equally frequent in all subtypes. Instead, HTMB (≥5 Muts/Mb) is more frequent in TNBC. BCs with HTMB had a different molecular landscape. Overall, several genes are recurrently down-regulated in HTMB group, and this is at least partly due to miRNA regulated post-trascriptional silencing, which might rapresents a new mechanism of immune escape. The positive association between TMB and immune genes in LumB, as well as the negative association in TN and LumA, suggest that immune editing and surveillance might be dependent on the molecular context. Citation Format: Luca Licata, Barbara Galbardi, Balázs Győrffy, Thomas Karn, Lorenzo Sica, Alessia Rognone, Patrizia Zucchinelli, Daniela Aldrighetti, Stefania Zambelli, Luca Gianni, Giampaolo Bianchini. Molecular differences between high and low tumor mutational burden (TMB) across breast cancer (BC) subtypes [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 P4-05-09.

Eribulin monotherapy in heavily pretreated metastatic breast cancer patients in real life.

Our retrospective, single-center study aimed at evaluating the efficacy and safety of eribulin in heavily pretreated metastatic breast cancer (MBC) in routine clinical practice. Twenty-eight patients treated with eribulin for MBC between May 2014 and November 2017 were included in our study. Clinical and biological assessment of toxicity was controlled at each visit. Tumor response was evaluated every three cycles of treatment. Median age at eribulin treatment was 52.5-year. Tumors were hormone receptor positive (71.4%), HER2-positive (10.7%), and triple negative (TN) (25%). Most of the patients (92.8%) presented with visceral metastases, mainly in the lymph nodes (57.1%) and liver (53.6%). Median previous metastatic chemotherapy line was 4 [1-7]. Median number of metastatic sites were 3 (1-4). Median number of eribulin cycles was 4. At the end of follow-up period, 36% of the patients were still alive. Eighteen patients died due to disease progression. The objective response rate was 21.5% with a 42.9% clinical benefit rate. Median progression-free survival and overall survival (OS) were 4 (95% CI: 2.7-5.2) and 14 (95% CI: 11.8-16.1) months, respectively. Treatment was well tolerated. None of the patients discontinued eribulin treatment due to toxicity. The most commonly reported toxicities were asthenia (71.4%), peripheral neuropathy (67.9%), and neutropenia (46.4%). Eribulin is an effective new treatment option in heavily pretreated MBC, with a manageable toxicity profile. Our results confirm that treatment with eribulin is feasible and safe in real-world patients.

Efficacy and Safety of Nab-Paclitaxel in the Treatment of Metastatic Breast Cancer: A Real-Life Experience

Aims: Evaluate safety and efficacy of nab-paclitaxel in pre-treated metastatic breast cancer (MBC) patients in a real-life setting. Patients and Methods: This single centre perspective non-comparative trial evaluated MBC patients treated with nab-paclitaxel. Primary endpoint was safety. Secondary endpoints were: overall response rate, progression free survival (PFS) and overall survival (OS). Results: 31 patients were enrolled. The main toxicities were fatigue (78%), pain (52%), neutropenia (42%) and febrile neutropenia (36%). The median OS was 10.2 months and median PFS was 4.5 months. A partial response was observed in 19.3% of patients and a stable disease in 38.7% of cases; the clinical benefit rate was 58%. Conclusions: Nab-paclitaxel represents a valid therapeutic option for the treatment of highly pre-treated MBC patients.

BP-C1 in treatment of pretreated metastatic breast cancer: A meta-analysis of two randomized, double-blind and placebo-controlled multicenter studies.

12 Background: To compare the effect of BP-C1 versus equal looking placebo in heavily pre-treated metastatic breast cancer (MBC) patients and to evaluate the efficacy of BP-C1 according to number of negative receptors. Methods: The study sample consisted of 61 patients from two randomized, double blinded and placebo controlled multicentre studies with semi-cross-over design. By randomization, 31 patients were allocated to BP-C1 and 30 to equal looking placebo treatment for 32 days. Twenty-five of the 30 patient allocated to placebo were switched to BP-C1 after finalizing the placebo period. A joint sample of 56 patients received one daily intramuscular injection of 0.07 ml/kg BW of BP-C1 for at least one cycle of 32 days. Receptor status including Estrogen, Progesterone and Human epidermal growth factor receptor was analysed prior to entering the study and available in 54 of the 56 patients. CT scans were performed at screening and after every 32-days of treatment, and were blindly analysed by one independent radiologist. The sum of target lesion diameters (SLD), RECIST classification and disease control rate (DCR) defined as patients obtaining at least stabile disease (SD) at the end of treatment was the main variables. Results: The SLD increased non-significantly by 1.5mm (5.7%) in the BP-C1 group and significantly (p &lt; 0.001) by 13.6 mm (26.2%) in the placebo group during the 32 days of treatment. The difference between groups with respect to SLD and DCR was significant in favour of BP-C1 (p &lt; 0.001). The tumour growth in the joint BP-C1 group was 2.5mm (5.9%) and DCR was 89.1% [95% CI: 38.1 – 96.0]. Nine of the 56 patients reported 26 Adverse Events (AE) related to BP-C1; all of mild to moderate degree. SLD increased 16.2% (p = 0.03) in patients with three positive receptors, 7.5% (p = 0.02) in the group with one negative receptor, 2.5% in the group of two negative receptors and 0.8% in triple negative patients. The tumor growth declined with increasing number of negative receptors (r = -0.26; p = 0.05). Conclusions: BP-C1 treatment of pre-treated MBC patients controlled the cancer growth with few mainly mild AE’s. The BP-C1 efficacy increased with the number of negative receptors. Clinical trial information: NCT03603197. Clinical trial information: NCT02783794.

Abstract 300: A new combination therapy to treat metastatic breast cancer

Abstract Poly (ADP-ribose) polymerase (PARP) resulting poly (ADP-ribosyl)ation is an early player in modification of proteins detected at single strand breaks and double strand breaks contributing to DNA repair. PARP1, 2 and 3 are involved in this process. However, PARP3 is unique in that, it is also required for efficient mitotic progression, specifically in stabilization of the mitotic spindle. The vinca alkaloids such as vinorelbine, arrest cells in metaphase due to inhibition of the assembly and dynamics of microtubules. Nontoxic concentrations of 2 PARP3 inhibitors, ME-0328 and olaparib, sensitized various her-2 negative and triple negative breast cancer cell lines greater than or equal to 10 fold to vinorelbine associated with potentiation of vinorelbine’s interaction with tubulin and also vinorelbine-induced PARP3 inhibition, mitotic arrest, and apoptosis without evidence of a DNA repair mechanism involved in this sensitization (Sharif-Askari B et al. Breast Cancer Res Treat. 2018 Nov;172(1):23-32). Eribulin is a Halichondrin B analogue, an antitubulin drug, with a unique mechanism of action; it inhibits microtubule dynamics via a novel mechanism of action which seems to involve binding to a unique site on tubulin resulting in the suppression of microtubule polymerization without affecting depolymerization along with sequestration of tubulin into nonfunctional aggregate. After impressive results in phase III trials (including one of the rare trials to show prolongation of survival in comparison to standard of care in heavily pretreated metastatic breast cancer patients) the U.S. Food and Drug Administration approved eribulin for treatment of patients with metastatic breast cancer. PARP3 inhibitors again sensitized at least 5 fold her-2 negative and triple negative breast cancer cell lines to eribulin. We will do similar studies with eribulin as we have done with vinorelbine including in-vivo studies. These studies could define a new therapy in the treatment of metastatic triple negative and ER+/her-2 negative breast cancer. The inhibition of PARP3 may increase the sensitivity of tumor cells to mitotic spindle poison chemotherapies. Our results should stimulate development of specific PARP3 inhibitors for clinical use. Citation Format: Bahram Sharif-Askari, Raquel Aloyz, Lawrence Panasci. A new combination therapy to treat metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 300.

A GINECO randomized phase II assessing addition of an aromatase inhibitor to oral vinorelbine in pretreated metastatic breast cancer patients.

1043 Background: For ER+/HER2- metastatic breast cancer (mBC), efficacy of endocrine therapy + chemotherapy combination remain an open question. We hypothesized that continuing ER targeted therapy after progression in combination with chemotherapy may improve disease control. The objective of the CHEOPS trial was to assess the benefit of adding aromatase inhibitor (AI) to metronomic chemotherapy,oral vinorelbine, 50mg/3 time a week (OV) for AI pre-treated, ER+/HER2- mBC patients. Methods: Eligible patients had to have progressed on endocrine therapy and one or two lines of chemotherapy. They were randomized between vinorelbine (OV) and vinorelbine + AI (OV+AI). Primary end point was progression-free survival (PFS). To show an increase of median PFS (from 3.5 to 5.5 month, HR 0.636), with alpha = 5% and power = 80%, 130 evaluable patients were needed. Results: 121 patients were Included (OV = 61; OV+AI = 60). Median age was 68 (range: 49-87), Median time from metastatic diagnosis was 3.2 years (range 0 - 16.9). 109 patients (90%) had visceral metastases. They all had previously received an AI and had been treated with one line (N = 66, 54.5%), or 2 lines (N = 55, 45.5%) of chemotherapy. Median PFS was increased from 2.3 months with OV to 3.7 months with OV+AI, but this difference was not significant (HR 0.73 [95 % CI 0.50-1.06], log-rank test: P = 0.09) 81 patients (67%) had at least one adverse event (AE) of grade ≥ 3 (40 (66%) for OV vs 41 (68%) for OV+AI). The most common grade ≥ 3 AE were: GT gammas (23%), neutropenia (18%), arterial hypertension and lymphopenia (17%). The occurrence of 3 toxic deaths (OV = 1; OV+AI = 2) secondary to febrile aplasia motivated the early cessation of this clinical trial. 9 patients (5 OV (10%) and 4 OV+AI (8%) presented an objective complete or partial response. Conclusions: The addition of AI to OV over OV alone in AI resistant mBC was associated with a non-significant improvement of PFS, but both PFS are lower than expected. Metronomic OV schedule, at 50 mg three times a week, requires close biological monitoring. The question of hormonal treatment and chemotherapy combination remains open. Clinical trial information: EudraCT Number: 2015-000401-39.

Low-dose metronomic chemotherapy (LDMC) as an efficient treatment option in metastatic breast cancer: Results of an exploratory case-control study.

e12578 Background: There is a growing importance of low-dose metronomic chemotherapy (LDMC) in metastatic breast cancer (MBC). In this retrospective case-control-analysis we compared the efficacy of LDMC and conventional chemotherapy in MBC. Methods: Each LDMC patient receiving oral cyclophosphamide (CTX) (50 mg daily) and methotrexate (MTX) (2.5 mg every other day) was matched with two patients who received conventional chemotherapy. Age, number of chemotherapy lines and metastatic lesions as well as hormone receptor (HR) status were considered as matching criteria. Primary endpoint was disease control rate greater than 24 weeks (DCR). Secondary endpoints were DCR in subgroups (number of chemotherapy lines, number of different metastatic lesions and HR status), progression-free survival (PFS) and duration of response (DoR). Results: A total of 35 cases and 70 controls entered the study. 31% patients with LDMC and 26% patients with conventional chemotherapy showed DCR (p = 0.644). Among younger patients DCR was 41% in LDMC vs. 30% in the control group (p = 0.534). In addition, DCR was achieved in 35% vs. 27% patients with ≤ 2 chemotherapy lines (p = 0.560) and in 36% vs. 20% patients with ≤ 2 different metastatic lesions (p = 0.168), respectively. In the triple negative group 30% LDMC vs. 5% control patients showed DCR (p = 0.095). PFS was 12.0 vs. 13.5 weeks (p = 0.415), DoR was 26.5 vs. 20.5 weeks (p = 0.628), respectively. Conclusions: In this retrospective case-control study we demonstrated a similar efficacy of LDMC compared to conventional chemotherapy in the treatment of MBC. Moreover, no significant differences were found in the subgroups studied. Therefore, the concept of LDMC may also be a treatment option in both younger and non-heavily pre-treated MBC patients who do not need rapid remission.

Abstract PD1-03: Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in HER3-overexpressing metastatic breast cancer: Updated results of a phase 1/2 trial

Abstract Background: Human epidermal growth factor receptor 3 (HER3) is overexpressed in a variety of solid tumors, including breast cancer. However, there are no approved HER3-targeted anti-cancer therapies. U3-1402 is a HER3-targeted antibody drug conjugate with a novel peptide-based cleavable linker attached to a potent topoisomerase I inhibitor payload. It has a high drug-to-antibody ratio (7:1 to 8:1), a novel linker which is stable in plasma and selectively cleaved by lysosomal cathepsins up-regulated in cancer cells, and a payload with a short systemic half-life. The ongoing, phase 1/2 study (NCT02980341) was initiated to evaluate the safety, tolerability, and efficacy of U3-1402 in HER3-overexpressing metastatic breast cancer (MBC). The study has 3 parts: Dose Escalation, Dose Finding, and Dose Expansion. Here we report updated results from Dose Escalation and Dose Finding. Methods: In Dose Escalation, the dose of U3-1402 was escalated based on dose-limiting toxicity data (between 1.6 and 8.0 mg/kg) and guided by the modified Continuous Reassessment Method. In Dose Finding, patients were treated with 1 of 2 doses (4.8 mg/kg or 6.4 mg/kg) identified during Dose Escalation. In both parts, U3-1402 was administered via IV infusion in 21-day cycles. The primary objectives were to determine the safety and tolerability of U3-1402, the maximum tolerated dose (MTD), and the recommended dose for expansion. Efficacy assessments included investigator-assessed objective response rate (ORR; proportion of complete response [CR] + partial response [PR]) per RECIST v1.1 and disease control rate (DCR; proportion of CR + PR + stable disease). Efficacy-evaluable patients received ≥1 dose of U3-1402 and had pre- and post-treatment tumor assessments. Pharmacokinetics and the anti-drug antibodies were also assessed. Results: As of 1 June 2018, a total of 42 patients received U3-1402 across Dose Escalation and Dose Finding (34 and 8 patients, respectively). Overall, 12 patients have discontinued treatment (9 due to progressive disease, 1 due to clinical progression, 1 due to Grade 2 pneumonitis, and 1 due to withdrawal of consent). A total of 30 patients remain on treatment (33.3% [14/42] for ≥6 months). The median (range) age was 54.5 (30–81), and majorities of patients had an ECOG performance status of 0 (76.2%; 32/42) and had received ≥5 prior anti-cancer regimens (78.6%; 33/42). Among efficacy-evaluable patients, the ORR was 46.3% (19/41) and the DCR was 90.2% (37/41). Grade ≥3 treatment-related AEs (TEAEs) were reported in 61.9% (26/42) patients. TEAEs (&amp;gt;50% in treated patients) regardless of causality (any grade, Grade ≥3) included nausea (83.3%, 4.8%), thrombocytopenia (71.4%, 33.3%), decreased appetite (64.3%, 7.1%), neutropenia (59.5%, 26.2%), and leukopenia (57.1%, 19.0%). The MTD was not reached; dose limiting toxicities included events of decreased platelet count and increases in AST or ALT. Conclusions: In a preliminary analysis of this ongoing phase 1/2 clinical trial, U3-1402 demonstrated antitumor activity in a substantial number of heavily pretreated HER3-expressing MBC patients, and U3-1402 treatment was associated with a manageable safety profile. Citation Format: Masuda N, Yonemori K, Takahashi S, Kogawa T, Nakayama T, Iwase H, Takahashi M, Toyama T, Saeki T, Saji S, Inoue K, Onuma H, Tajima N, Shiose Y, Chen S, Guevara F, Yu C, Ueno S, Iwata H. Single agent activity of U3-1402, a HER3-targeting antibody-drug conjugate, in HER3-overexpressing metastatic breast cancer: Updated results of a phase 1/2 trial [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 PD1-03.