Pretreated Breast Cancer Patients Research Articles

Abstract PO1-04-01: Phase 1 dose escalation study of ARX788, a next-generation anti-HER2 antibody drug conjugate, in heavily pretreated breast cancer patients

Abstract Introduction: ARX788 is a next-generation anti-HER2 antibody-drug conjugate (ADC) conjugated to amberstatin269 (AS269), a potent cytotoxic tubulin inhibitor. ARX788 is highly stable with nearly identical PK profiles for the total ADC and the total antibody due to proprietary site-specific oxime conjugation chemistry. The stability of ARX788 results in limited systemic toxicity and increased targeted delivery of payload to tumor cells. Clinical benefit of ARX788 has been observed in patients (pts) with HER2-positive (HER2-pos) breast cancer (BC) in multiple clinical trials and recently in a randomized, controlled, phase 3 registrational trial conducted in China. Methods: ARX788-1711 (NCT03255070)was a phase 1 dose-escalation study of ARX788 monotherapy in pts with advanced solid tumors with HER2 expression. There was no limit to the number of prior therapies. An objective of the trial was investigating the safety and tolerability of ARX788 in pts with BC. Results: Between August 2020 and June 2023, 42 pts with HER2-pos and HER2-low BC with a median of 6 prior lines of therapy received intravenous ARX788 at either 1.5, 1.6, or 1.7 mg/kg every 21 days (Q3W) or every 28 days (Q4W). Treatment regimens were combined for these analyses. ARX788 was generally well tolerated. Most adverse events (AEs) were grade (Gr) 1 or 2, the most common being ocular, alopecia, nausea, and fatigue. Gr3 treatment-related AEs (TRAEs) occurred in 23.8% of pts and included nausea, ocular, AST and ALP increase (4.8% each); one pt (2.4%) had Gr3 pneumonitis/interstitial lung disease. A Gr3 ocular SAE occurred 48 days after the pt’s last study dose and was resolving 9 days after onset. There were no Gr4 or Gr5 events. Treatment discontinuation due to drug-related AEs occurred in 7.1% of pts. Overall response rate (ORR) per RECIST v1.1 was analyzed in groups by HER2-low or HER2-pos tumor status. In pts with HER2-pos BC (n=11) the ORR was 54.5% (4 confirmed, 2 unconfirmed); in pts with HER2-low BC (n=30) the ORR was 23.3% (5 confirmed, 2 unconfirmed). The disease control rate (confirmed complete or partial response + stable disease) was 81.8% and 76.7%, for HER2-pos and HER2-low BC, respectively. Six of 9 pts with confirmed responses had a duration of response greater than 5 months. Six of eight pts with prior trastuzumab deruxtecan (T-DXd) exposure also had prior trastuzumab emtansine (T-DM1). Two pts with prior T-DM1 and T-DXd had significant target lesion reductions of 55% and 32%; these were a HER2-low pt with 6 prior cancer therapy regimens and a HER2-pos pt with 9 prior cancer therapy regimens, respectively. Both pts came off treatment before response confirmation. As of the data cut-off (19 Jun 2023), 4 of 9 confirmed responders remain on treatment and continue to experience clinical benefit including one pt with prior T-DM1 exposure with a durable response of 15.8 months. Importantly, significant target lesion reductions were observed in heavily pretreated pts who also received prior T-DXd and T-DM1. Discussion: Based on the promising safety and antitumor activity of ARX788 in this heavily pretreated pt population, a phase 2 study is open (NCT04829604) and enrolling pts with HER2-pos BC who have been previously treated with T-DXd. Citation Format: Sophia Frentzas, Haesong Park, George Budd, Vinod Ganju, Catherine Shannon, Sara Hurvitz, Katharine Cuff, Peter Lau, Richard Eek, Joyce O'Shaughnessy, Fran Boyle, Sandra Aung, Colin Hessel, Janice Lu. Phase 1 dose escalation study of ARX788, a next-generation anti-HER2 antibody drug conjugate, in heavily pretreated breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-01.

Patient-reported outcomes for measuring the quality of life in advanced breast cancer treated with third-line and beyond chemotherapy-based regimens: A national cross-sectional study.

1103 Background: Prolongation of survival and maintenance of quality of life (QoL) are the primary therapeutic goals in advanced breast cancer. Around 10% of adverse events (AEs) in the CTCAE are symptomatic AEs (e.g., nausea, sensory neuropathy), which can severely and directly affect the QoL of patients. However, seldom evidence mapped the QoL and symptomatic AEs utilizing patient-reported outcomes (PROs) in heavily pretreated breast cancer patients. This study aimed to investigate the PROs for measuring the QoL and symptomatic AEs of advanced breast cancer treated with third-line and beyond chemotherapy-based regimens in China. Methods: This national survey enrolled patients with advanced breast cancer receiving third-line and beyond chemotherapy-based regimens in 59 centers all over China from March to April in 2021. Each patient filled out a questionnaire containing demographic information, medical history, EORTC-QLQ-C30, and symptomatic AEs. The symptomatic AEs included fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, alopecia, fever, and limb numbness. The range method was used for the linear conversion of the PRO scores, which were converted into standardized scores of 0 to 100. Results: This study enrolled 1015 patients with the median age of 52 years. The QoL of all patients were poor, with the global health status score of 52.4±17.7 (Table). All the symptomatic AE scores were low among the patients. However, no significant differences were observed in global health status and symptomatic AEs between mono-chemotherapy and multi-agent chemotherapy (All P>0.05). Conclusions: The QoL of advanced breast cancer patients treated with third-line and beyond chemotherapy were poor, especially in symptomatic AEs. In addition, the EOTRC-QLQ-C30 scale appears to underestimate the differences in symptomatic AEs between mono-chemotherapy and multi-agent chemotherapy, probably due to a lack of sensitivity of the scale, which fails to match the actual clinical observations of the PROs and QoL. Therefore, new scales need to be developed for the evaluation of symptomatic AEs and QoL in advanced breast cancer. [Table: see text]

Abstract P5-18-10: Mecapegfilgrastim for primary prophylaxis of neutropenia in 355 HER2+ breast cancer patients treated with neoadjuvant docetaxel in combination with trastuzumab and/or pyrotinib: Exploratory analysis from randomized, double-blind, phase 3 PHEDRA study

Abstract Background: A dose relationship may exist for both antitumor activity and toxicity of docetaxel in breast cancer (BC) patients, while 86% grade 4 neutropenia and 12% febrile neutropenia (FN) were reported when pretreated advanced breast cancer (ABC) patients received 100 mg/m2 docetaxel monotherapy without hematopoietic support. PHEDRA was a randomized, double-blind, multicenter, phase 3 study comparing the efficacy and safety of adding pyrotinib to trastuzumab and docetaxel as neoadjuvant treatment in women with HER2+ early or locally ABC (ClinicalTrials.gov: NCT03588091). We conducted this exploratory analysis to evaluate the effectiveness of mecapegfilgrastim, a long-acting recombinant human granulocyte colony-stimulating factor (rhG-CSF), as primary prophylaxis for neoadjuvant chemotherapy-induced neutropenia in BC patients. Methods: Patients with HER2-positive early or locally ABC were randomly assigned (1:1) to pyrotinib arm receiving 4 neoadjuvant cycles of docetaxel (100 mg/m2 iv d1 q3w), trastuzumab (8 mg/kg iv, cycle 1 d1, then 6 mg/kg d1 q3w), and pyrotinib (400 mg po qd, d1-21, q3w) or placebo arm with placebo, trastuzumab and docetaxel. Per protocol, patients were required to receive a single, 6-mg fixed dose of mecapegfilgrastim on Day 2 of each cycle. Other G-CSF was permitted if mecapegfilgrastim was unavailable at the local center or patients occurred mecapegfilgrastim intolerance. The incidence of neutropenia, FN, time to first neutropenia onset, duration per neutropenia event and cumulative neutropenia duration during neoadjuvant treatment period; and the incidences of grade 3/4 neutropenia, FN and decreased WBC count in Cycle 1 to 4 (C1-4) were presented. The data cutoff date was April 30, 2021. Results: Between July 23, 2018 and January 8, 2021, 355 patients were randomized (pyrotinib arm, n=178; placebo arm, n=177). Among them, 291 (82.0%) patients received a single, 6-mg fixed dose of mecapegfilgrastim in Cycle 1 and 270 (76.1%) patients received mecapegfilgrastim in each of the 4 cycles. Grade 3/4 neutropenia was reported in 33 (18.5%) patients in the pyrotinib arm and 36 (20.3%) patients in the placebo arm. Five (2.8%) patients in the pyrotinib arm and 2 (1.1%) patients in the placebo arm developed FN (5 FN occurred in C1; 2 FN occurred in C2). Median duration of grade 3/4 neutropenia was 3 days in the pyrotinib group and 3 days in the placebo group. Median cumulative duration of grade 3/4 neutropenia was 4 days and 3 days in the pyrotinib group and the placebo group, respectively. Grade 3/4 neutropenia mainly occurred during the first cycle of treatment for both pyrotinib (13.5%) and placebo arm (15.8%), reduced in the second cycle (5.9% vs 4.0%) and thereafter (C3: 1.8% vs 3.4%; C4: 2.4% vs 1.7%). Similar trends were observed for grade 3/4 WBC count decreased in Cycle 1 to 4. No grade 4 infection occurred. Overview of neutropenia, FN and WBC count decreased was summarized in Table 1. Consistent findings were observed in 291 mecapegfilgrastim treated patients. Conclusion: The exploratory analysis demonstrated 6-mg fixed dose of mecapegfilgrastim was effective when administrated as primary prophylaxis for neoadjuvant chemotherapy-induced neutropenia, which could be considered as a new treatment option for its advantage of once-per-cycle dosing and convenient dose management. Table 1.Overview of neutropenia, febrile neutropenia and WBC count decrease during neoadjuvant treatment period.Docetaxel+Trastuzumab+Pyrotinib(N=178)Docetaxel+Trastuzumab+Placebo (N=177)All randomized patients(N=355)Neutropenia, n (%)Any grade57 (32.0)54 (30.5)111 (31.3)Grade 16 (3.4)5 (2.8)11 (3.1)Grade 218 (10.1)13 (7.3)31 (8.7)Grade 315 (8.4)20 (11.3)35 (9.9)Grade 418 (10.1)16 (9.0)34 (9.6)Median time to first onset (IQR), days7 (6-63)6 (6-49)7 (6-53)Median duration per grade 3 or higher neutropenia, days (range)3 (1-16)3 (2-12)3 (1-16)Median cumulative duration of grade 3 or higher neutropenia, days (range)4 (2-16)3 (2-14)3 (2-16)FN, n (%)5 (2.8)2 (1.1)7 (2.0)Grade 3 or higher neutropenia, n (%) *Cycle 124 (13.5)28 (15.8)52 (14.6)Cycle 210 (5.9)7 (4.0)17 (4.9)Cycle 33 (1.8)6 (3.4)9 (2.6)Cycle 44 (2.4)3 (1.7)7 (2.1)Grade 3 or higher FN, n (%) *Cycle 12 (1.1)2 (1.1)4 (1.1)Cycle 22 (1.2)02 (0.6)Cycle 3000Cycle 4000Grade 3 or higher WBC count decreased, n (%) *Cycle 120 (11.2)20 (11.3)40 (11.3)Cycle 28 (4.7)2 (1.1)10 (2.9)Cycle 32 (1.2)1 (0.6)3 (0.9)Cycle 44 (2.4)2 (1.1)6 (1.8)Note: IQR, interquartile range; FN, febrile neutropenia; WBC, white blood cell.*The denominator indicates number of patients with mecapegfilgrastim for prophylaxis use in this cycle. Citation Format: Min He, Benlong Yang, Jiong Wu, Zhenzhen Liu, Hongjian Yang, Jinhai Tang, Kun Wang, Yunjiang Liu, Haibo Wang, Peifen Fu, Shuqun Zhang, Qiang Liu, Zefei Jiang, Shusen Wang, Jian Huang, Chuan Wang, Shu Wang, Yongsheng Wang, Linlin Zhen, Xiaoyu Zhu, Shulin Liu, Ping Yan, Jianjun Zou. Mecapegfilgrastim for primary prophylaxis of neutropenia in 355 HER2+ breast cancer patients treated with neoadjuvant docetaxel in combination with trastuzumab and/or pyrotinib: Exploratory analysis from randomized, double-blind, phase 3 PHEDRA study [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 P5-18-10.

Abstract PS10-51: TAA013 a trastuzumab antibody drug conjugate phase I dose escalation study in recurrent her2 positive breast cancer

Abstract Background: A phase 1 dose escalation study of TAA013, an antibody drug conjugate linking trastuzumab to a cytotoxic small molecule, DM1, through an SMCC linker, in previously treated recurrent Her2 positive breast cancer patients. Material and Methods: This phase I study follows the traditional 3+3 design, dosing started at 0.6mg/kg, followed by 1.2, 2.4, 3.6, 4.8mg/kg, one intravenous infusion was given every 3 weeks, the initial infusion had to be over 90 minutes, infusion times were later shortened if treatment was well tolerated. The subsequent recommended dose would be expanded to include at least 10 patients. Patients were observed for dose-limiting toxicity (DLT) during a 21-day DLT observation period. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Maximum-tolerated dose (MTD) was defined as the highest dose level that resulted in a DLT in no more than 1 of 6 patients. Study endpoints included safety and tolerability, pharmacokinetic and immunogenicity parameter evaluation, with preliminary evaluation of efficacy. Results: The study enrolled 22 female patients with histologically confirmed Her-2 positive metastatic breast cancer, median age of 50yrs (25-67), median time from initial diagnosis to TAA013 dosing was 39 months (5-99), median prior treatment regimen was 4 (2-10), all had received trastuzumab for a mean of 8.2 months (2-10), alone or in combination with chemotherapy, other prior Her2 targeting drugs given included pertuzumab (2), lapatinib (7), and pyrotinib (8). All patients received at least 2 (median of 6 infusions, range of 1-15) infusions, except for the last 4.8mg/kg patient, but all patients passed the dose limiting toxicity (DLT) observation period of 21 days. There were no dose limiting toxicities, no serious adverse events, nor that resulting in mortality, the maximum tolerated dose was not reached. The most common treatment emergent adverse events (TEAE) included 9 (40.9%) grade 1-2 infusion reactions associated with fever(5) and/or chills(1), the reaction often abated in subsequent cycles. There were no grade 4 TEAE, but there were 3 grade 3 thrombocytopenia, one grade 3 neutropenia, and one grade 3 hyperbilirubinemia which all recovered for the patients to continue treatment, there was also one grade 3 dermatitis in a patient with a history of chronic dermatitis. Antibody drug antibodies were not detected emanating from the TAA013 therapy. Pharmacokinetic studies included evaluation of TAA013, trastuzumab and DM1. Preliminary efficacy evaluation in the 2.4-4.8mg/kg dosing group of heavily pretreated patients resulted in 2 partial responses, including patients who had previously received pyrotinib therapy. Conclusion: TAA013 is a Her2 targeting antibody drug conjugate that is safe and tolerable, with efficacy demonstrated in heavily pretreated Her2 positive breast cancer patients. Keywords: breast cancer, antibody drug conjugates, TAA013. Citation Format: J M Liu, Y M Yin, Hao Wu, W Li, X Huang, XX Li. TAA013 a trastuzumab antibody drug conjugate phase I dose escalation study in recurrent her2 positive breast cancer [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 PS10-51.

A prognostic 10-miRNA risk score (10-miRNA RS) in predicting neoadjuvant chemotherapy sensitivity of luminal breast cancer.

3139 Background: The 10-miRNA risk score is a prognostic 10-gene expression signature specifically developed in luminal breast cancer associated with relapse-free survival. Since high-risk patients identified by10-miRNA RS had worse prognosis but better outcome with chemotherapy than low-risk patients (Gong C et al, EBioMedicine. 2016), this model may facilitate personalized therapy-decision making for luminal breast cancer patients. Therefore, we seek to validate whether high-risk group are more sensitive to chemotherapy than low-risk group by assessing the predictive value of 10-miRNA RS for pathological complete response (pCR) in patients receiving neoadjuvant chemotherapy (NAC). Methods: The 10-miRNA gene expression and clinicopathological data were prospectively gathered from 251 pretreated biopsy-diagnosed luminal breast cancer patients from 4 breast cancer centers. Formalin-fixed paraffin-embedded tissues from basal line biopsy were used for the detection of 10-miRNA expression to calculate the RS. The correlation between pCR and the 10-miRNA RS classification were identified. Results: In this prospective, multicenter study, the overall pCR rate was 13.6% (34/251). The 10-miRNA RS of the pCR group was significantly higher than the non-pCR group ( P = 0.015). Fifty-one percent of patients were classified as low-risk according to the 10-miRNA RS classification and 49% as high-risk with a RS cut-off point of 2.144. The 10-miRNA RS classification was associated with a pCR rate of 9.4% in the low-risk group and 17.8% in the high-risk group ( P = 0.041). The correlation between the pCR and the 10-miRNA RS classification was significant in subgroup analysis stratified by molecular subtypes (8% vs. 13.2% in luminal B1; 14.7% vs. 30.1% in luminal B2; no pCR was observed in all 13 luminal A subtype). In multivariate analysis, the 10-miRNA RS remained significantly associated with pCR and independent from subtype, ki67 and other clinicopathological characteristics. Conclusions: 10-miRNA RS clearly defined that high-risk patients are more sensitive to chemotherapy which leads to a higher pCR rate in NAC patients. Thus, 10-miRNA RS is not only a prognostic factor but an effective method in determining whether a patient would undergo surgery or receive NAC prior to surgery. Clinical trial information: ChiCTR-DDD-17013651.

Liposomal cisplatin response prediction in heavily pretreated breast cancer patients: A multigene biomarker in a prospective phase 2 study.

e13077Background: In an ongoing, open-label Phase 2 study liposomal cisplatin (LiPlaCis) was evaluated in metastatic breast cancer (mBC) patients selected by a cisplatin-specific mRNA-based drug re...

Abstract P1-14-06: Selective internal radiation therapy (SIRT) with Yttrium-90 resin microspheres and FOLFOX/5FU chemotherapy in pre-treated breast cancer patients with liver metastases: A retrospective analysis of response rates, times to progression and survival of patients treated in Manchester UK between 2010 and 2016

Abstract Background: SIRT is a globally licensed technique of Radio-Embolization (RE) of hepatic tumors via intra-arterial infusion of β-particle emitting Yttrium-90 (Y-90) radio-labelled microspheres. It increases response rates and hepatic time to progression in metastatic colorectal cancer when used in combination with 5FU/Oxaliplatin (FOLFOX) chemotherapy with acceptable toxicity profile. FOLFOX gives a radio-sensitizing effect and also controls disease outside the liver. Breast cancer liver metastases (BCLM) patients often have extra-hepatic disease and respond to multiple lines of systemic therapy and SIRT is infrequently used. Methods and patients Between 2010 and 2016 we treated 25 BCLM patients with Y-90 SIRT. Receptor status: 20 ER+ve/HER-2 -ve, 3 ER-ve/HER-2 +ve, 2 triple -ve. Eleven patients had liver only disease with 14 also having known extra-hepatic disease. Average number of previous lines of therapy in metastatic setting: chemotherapy = 2.4; endocrine = 1. Sixty-four % patients had prior Capecitabine (n=16); 12% platinum (n=3, all Carboplatin). Twenty patients received chemotherapy with SIRT: 17 had modified FOLFOX6 (Oxaliplatin/bolus 5FU day1, infusional 5FU day 1-3 (46 hrs); 3 patients had Modified de Gramont style 5FU alone. Five patients had no chemotherapy. Sir-spheres were inserted on day 2 of FOLFOX with the 5FU infusion pump continuing to day 3. Further 2-weekly FOLFOX chemo cycles were at clinician's discretion: average number delivered 3.8. Four patients had the liver treated in two halves, approximately 6 weeks apart. One patient received SIRT only to half the liver. Patients were imaged with PET-CT/CT before and 2-3 months after SIRT. Retrospective case note review was performed and data correlated to evaluate tumor response (RR); hepatic and extra hepatic progression free survival (HPFS and EHPFS) and overall survival (OS). Accurate toxicity data was not recorded. Results Hepatic CT response rates: PR 56% (n=14), SD 28% (n=7) and PD 16% (n=4). Hepatic PET response rates: CR 32% (n=8), PR 40% (n=10), SD 12% (n=3), PD 16%(n=4). (Overall PET liver disease control rate = 84%). Eight patients (32%) had extra-hepatic PD at first assessment. Of them, 4 had PR, 2 SD and 2 PD in the liver at that assessment. Two HER-2 +ve patients had brain metastases as first sign of PD within 75 days, an area not previously screened. Of 16 pre-treated with Capecitabine, liver CT response rates: 62.5% PR, 18.75% SD (n=10,3). Post SIRT/FOLFOX, average number of therapy lines: 2 for chemo and 0.75 for endocrine, with 8 patients still alive at time of censoring. Median OS: 766 HPFS: 210 days (CI 140-286). Median EHPFS in patients with extra-hepatic disease: 152 days (CI 96-636). Conclusions SIRT with FOLFOX in previously treated BCLM patients produces high response rates, excellent tumor control and time to progression in the liver with good overall survival. It does not seem to decrease the ability to give further lines of chemotherapy and can be considered as an option for breast cancer patients with liver metastases. Citation Format: Wilson G, Mullamitha S, Bentley D, Bell J, Mullan D, Carter L, Chittalia A, Howell S, Laasch H-U, Westwood T, Jeans S, Tipping J, Ryder D, Farquharson F, Arumugam P, Sheen A, Rajashanker B, Armstrong A, Misra V, Manoharan P, Lawrance J. Selective internal radiation therapy (SIRT) with Yttrium-90 resin microspheres and FOLFOX/5FU chemotherapy in pre-treated breast cancer patients with liver metastases: A retrospective analysis of response rates, times to progression and survival of patients treated in Manchester UK between 2010 and 2016 [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 P1-14-06.

Eribulin inhibits the growth of small cell lung cancer cell lines alone and with radiotherapy

ObjectivesSmall cell lung cancer (SCLC) patients of all stages are treated with etoposide and cisplatin or carboplatin with or without surgery or chest radiotherapy. Initial response rates are ≥70% however the majority of patients relapse and are resistant to additional therapies due to pan-resistance to these salvage therapies. Therefore, new treatments are urgently needed. The non-taxane microtubule inhibitor eribulin has produced responses in heavily pretreated breast cancer patients. We evaluated the efficacy of eribulin alone and in combination with radiation in a panel of SCLC cell lines established from patients prior to or after receiving chemotherapy and or radiation. Material and methodsGrowth inhibition by eribulin alone, radiation alone and the combination was assessed by MTS assay and clonogenic survival. Eribulin induced cell cycle arrest was evaluated by FACS. Apoptosis was evaluated by using the Caspase-GLO 3/7 luminescent plate assay and by the Vybrant apoptosis assay with analysis by FACS. ResultsEribulin mesylate inhibited the growth of all 17-SCLC lines at concentrations of ≤10 nM which is a clinically achievable dose. Growth inhibition was not significantly different between cell lines established prior to or after chemotherapy (p = .5). Concurrent eribulin + radiation induced a greater G2-M arrest, an increase in apoptotic cells and increased growth inhibition over radiation alone. ConclusionsEribulin was highly active alone and in combination with radiation in treatment naïve SCLC lines and lines established from previously treated patients. In vivo pre-clinical studies of eribulin alone and in combination with radiation should be considered in SCLC cell lines.

Unusual long-lasting cutaneous complete response to lapatinib and capecitabine in a heavily pretreated HER2-positive plurimetastatic breast cancer patient.

Lapatinib, in combination with capecitabine, has shown clinical activity in both first-line and refractory disease in patients with HER2-positive advanced breast cancer. Herein we describe the case of a plurimetastatic, heavily pretreated, HER2-positive breast cancer patient who experienced multiple cutaneous metastases successfully treated with lapatinib and capecitabine. An early complete response was obtained on all skin lesions, and no evidence of disease progression at other metastatic sites was observed for 22 months. The treatment was well tolerated, without dose-reductions or delays. In advanced breast cancer patients with skin metastases overexpressing HER2, previously treated with anthracyclines, taxanes and trastuzumab, lapatinib and capecitabine may represent a very active, safe and well-tolerated treatment option.

Radiotherapy improves serum fatty acids and lipid profile in breast cancer

BackgroundBreast cancer is a disease with diverse clinical symptoms, molecular profiles, and its nature to response its therapeutic treatments. Radiotherapy (RT), along with surgery and chemotherapy is a part of treatment in breast cancer. The aim of present study was to investigate pre and post treatment effects of radiotherapy in serum fatty acids and its lipids profile in patients with breast cancer.MethodsIn this comparative as well as follow up study, Serum fatty acids were performed by gas chromatography to investigate fatty acids and Microlab for analysis of lipid profile.ResultsAmong serum free and total fatty acids the major saturated fatty acids (SFAs) in serum lipids of breast cancer patients (pre and post treated) were stearic acid (18:0) and palmitic acid (16:0). These fatty acids contributed about 35-50% of total fatty acids. The decreased concentrations of linoleic acid (C18:2) and arachidonic acid (C20:4) with a lower ratio of C18:2/C18:1 was found in pretreated breast cancer patients as compared to controls. The n-3/n-6 ratio of breast cancer patients was decreased before treatment but it was 35% increased after treatment. In addition, plasma activity of D6 desaturase was increased in the breast cancer patients, while the activity of D5 desaturase was decreased. Increased levels of SFAs, monounsaturated fatty acids (MUFAs) and decreased polyunsaturated fatty acids (PUFAs) levels in breast cancer patients (pre and post treated) as compared to controls. Serum total cholesterol (TC) (224.4 mg/dL) and low density lipoprotein cholesterol (LDL-C) (142.9 mg/dL) were significantly increased in pretreated breast cancer patients but after the radiotherapy treatment, the TC (150.2 mg/dL) and LDL-C (89.8 mg/dL) were decreased.ConclusionIt seems that RT would have played a potential role in the treatment of BC. After RT the serum levels of PUFAs, TC, and LDL-C are improved. Our study reinforces the important role of RT in the management of BC.The level of PUFAs, TC, and LDL-C can be used as the biomarkers for early diagnosis in individuals with risk of breast cancer.

Abstract P6-11-09: Heavily pre-treated breast cancer patients show promising responses in the first in human study of the first-In-class fatty acid synthase (FASN) inhibitor, TVB-2640 in combination with paclitaxel

Abstract Introduction FASN inhibition is a novel approach to cancer treatment involving selective disruption of palmitate biosynthesis that, in tumor cells, leads to apoptosis. TVB-2640 is an oral, first-in-class, small molecule reversible inhibitor of FASN that demonstrates in vivo antitumor effects. We previously reported the results of dose escalation and now present evidence of preliminary activity in breast cancer patients treated in the dose expansion cohort. Methods This ongoing international, multicenter Phase I trial enrolls patients (pts) with advanced solid tumors with adequate organ function. TVB-2640 is given orally once daily at the MTD (100 mg/m2) as monotherapy (mono) or in combination (combo) with weekly IV paclitaxel (80 mg/m2). Results The most common AE's observed [mono, N=53; combo, N=47] were: alopecia (57%), palmar-plantar erythrodysesthesia (PPE) (36%), dry eye (13%) and increased lacrimation (11%). Gr. 3 toxicities include corneal edema (3%) and PPE (10%). Other toxicities were ≤ Gr. 2 and only minor GI symptoms occurred. All toxicities were reversible on dose interruption and no enhancement of common paclitaxel toxicity was observed when given with TVB-2640. Rare cases of pneumonitis in combination have been observed but the contribution of TVB-2640 to this effect is uncertain. 14 breast cancer patients were enrolled and treated in combination with weekly paclitaxel while 3 breast patients were given monotherapy (during the dose escalation phase). Among patients treated in combination, three (3) confirmed RECIST partial responses (cPR) were seen and multiple cases of prolonged stable disease (SD) (≥16 wks) despite heavy pre-treatment and taxane resistance in all but 2 cases. One ER+, PR+, Her2+ patient achieved a cPR and was on study for 26 weeks. One ER-/PR-/Her2+ patient whose previous best response to paclitaxel treatment was SD for 24 weeks, reached a cPR at week 12, discontinued paclitaxel at week 21 and remains on monotherapy TVB-2640 with a sustained cPR at week 29. The third responder with cPR is an ER+, PR+, HER2- patient whose previous taxane treatment lasted 15 weeks (response unknown) and she remains on study at week 24. Of the remaining 11 patients, 10 achieved SD > 12 weeks and 8 of the 10 maintained that response for 16-45 weeks. The ongoing SD patient at week 45, discontinued paclitaxel at week 35 and remains on monotherapy TVB-2640. Summary TVB-2640 demonstrated multiple cPRs and prolonged SD when combined with weekly paclitaxel in 93% of patients treated. Further exploration of response in patients recently progressed on a taxane (progression within the prior 6 months) and safety with TVB-2640 in combination with docetaxel is being explored. Citation Format: Brenner AJ, Falchook G, Patel M, Infante JR, Arkenau H-T, Dean EM, Borazanci E, Lopez JS, Moore K, Schmid P, Frankel AE, Jones S, McCulloch W, Kemble G, Grimmer K, Burris H. Heavily pre-treated breast cancer patients show promising responses in the first in human study of the first-In-class fatty acid synthase (FASN) inhibitor, TVB-2640 in combination with paclitaxel [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 P6-11-09.

Eribulin plus trastuzumab in pretreated HER2-positive advanced breast cancer (ABC) patients: Results on safety and efficacy—An Italian multicenter experience.

e12087Background: Chemotherapy (CT) plus targeted therapy is the established treatment for HER2 overexpressing breast cancer (BC) patients (pts). The debate about anti-HER2 combination beyond standard therapies is still unresolved. Limited data regarding the safety and activity of the combination of eribulin and trastuzumab (E/T) in pretreated HER2-positive advanced breast cancer (ABC) are available. The aim of this observational, retrospective, multicenter study was to examine the tolerability and the clinical activity of eribulin plus trastuzumab in this setting. Methods: Pts treated with eribulin mesylate (1.23 mg/m2 administered via intravenous infusion on Days 1 and 8 each 21-day cycle) plus standard dose of trastuzumab (16 pts received 3-week schedule: 8 mg/kg load, 6 mg/kg q 3 weeks; 3 pts received weekly schedule: 4 mg/kg load, 2 mg/kg q week) were included. Data on overall response rate (ORR), progression free survival (PFS), post-progression survival (PPS), overall survival (OS) and safety were ...

Real-life effectiveness of T-DM1 in heavily pretreated HER2-positive advanced breast cancer patients: An Italian observational study.

e12019Background: T-DM1 showed remarkable activity in metastatic (m) HER-2 positive breast cancer (BC) and it recently was approved for clinical use in patients (pts) who previously failed trastuzumab and taxanes. The impact of drug prescription in real life compared with the findings reported in clinical trials exerting a strict accrual criteria has been rarely assessed. We investigated use and effectiveness of T-DM1 in daily practice. Methods: We included all pts with HER2-positive mBC, diagnosed in 12 Italian oncology hospitals between 2013 and 2015. Our aim was to assess the actual use of T-DM1 in HER2 positive mBC pts and its efficacy in clinical practice. Results: The data of 119 pts were retrospectively collected. The median age was 49 years (28-78), visceral metastases were present in 91 pts (77%) and brain metastases in 44 (37%). It is noteworthy that 29 pts (24%) received T-DM1 as second-line, 42 (35%) as third-line, and 43 (36%) as fourth- or further-line option. Moreover, 4 pts had TDM-1 as fi...

Initial experience with genomic profiling of heavily pretreated breast cancers.

Rapidly evolving advances in the understanding of theorized unique driver mutations within individual patient's cancers, as well as dramatic reduction in the cost of genomic profiling, have stimulated major interest in the role of such testing in routine clinical practice. The aim of this study was to report our initial experience with genomic testing in heavily pretreated breast cancer patients. Patients with primary or recurrent breast cancer managed at any of our five hospitals and whose malignancy had failed to respond to therapy or had progressed on all recognized standard-of-care options were offered the opportunity to have their cancer undergo next-generation sequencing genomic profiling. Of a total of 101 patients, 98 (97 %) had at least one specific genomic alteration identified. A total of 465 different somatic genetic abnormalities were revealed in this group of patients. Although 52 % of patients were found to have an abnormality for which an U.S. Food and Drug Administration (FDA)-approved drug was available, 69 % of patients had an FDA-approved agent for an indication other than breast cancer. The most common genomic alterations of potential clinical consequence were PIK3 (25 %), FGFR1 (16 %), AKT (11 %), PTEN (10 %), ERBB2 (8 %), JAK2 (6 %), and RAF1 (5 %). Almost all advanced breast cancers possess at least one well-characterized genomic alteration that might be actionable at the clinical level. Further, in most cases, a plausible argument can be advanced for the potential biological and clinical relevance of an FDA-approved antineoplastic agent not currently indicated in the treatment of breast cancer.

Eribulin mesylate in pretreated breast cancer patients: a multicenter retrospective observational study.

Background: Eribulin was recently approved in patients progressing after being treated with anthracyclines and taxanes and after two or more chemotherapy lines for advanced disease.Objectives: This multicenter observational retrospective study was performed in order to evaluate activity and tolerability of eribulin in real-world patient population.Methods: 133 advanced breast cancer patients pretreated with ≥ 2 chemotherapy lines for metastatic disease were retrospectively enrolled in the observational trial in 11 italian cancer centres.Results: A median of 5 cycles of eribulin (range, 1-15) were administered. Twenty-eight partial responses were observed, for an overall response rate of 21.1% (95%CI,14.1-28.0). A stable disease was recorded in 57 patients (42.8%), and a clinical benefit (response or stable disease lasting ≥ six months) was observed in 51 patients (38.3%, 95%CI, 30.1-46.6). The subgroup analysis showed that a significant improvement in term of partial response and clinical benefit was achieved when eribulin was administered in HER-2 negative tumors (p=0.01 and p=0.004, respectively) and when it is given as third-line (p=0.09 and p=0.02, respectively). Toxicity was manageable; fatigue is the most common side effect observed, usually of low-grade, and clearly cumulative-dose related.Conclusions: In this retrospective, observational analysis eribulin confirmed its efficacy and manageable tolerability even in real-world population and in heavily pretreated patients.

Abstract OT2-6-04: Dovitinib, a receptor tyrosine kinase inhibitor in combination with fulvestrant in postmenopausal endocrine resistant human epidermal growth factor receptor 2 negative (HER2-) / hormone receptor-positive (HR+) breast cancer: A phase II, randomized, double blind, placebo-controlled study

Abstract Background: Overcoming endocrine resistance is a critical goal in the treatment of HR+ breast cancer. Emerging in vitro evidence suggests that amplification and overexpression of fibroblast growth factor receptor 1 (FGFR1) is associated with endocrine resistance. Up to 8% of patients with HER2–/HR+ breast cancer have amplification of the FGFR1 gene. Dovitinib, a potent inhibitor of FGFR, as well as vascular endothelial growth factor receptor, and platelet-derived growth factor receptor, demonstrated antitumor activity in heavily pretreated breast cancer patients with FGF-pathway amplification. The objective of this study is to determine if dovitinib in combination with fulvestrant can improve outcomes in postmenopausal patients with endocrine resistant HER2-/HR+ breast cancer. Trial design: This multicenter, randomized, double-blind, placebo-controlled, phase II trial (NCT01528345) will enroll postmenopausal patients with HER2–/HR+ locally advanced or metastatic breast cancer. Patients are randomized 1:1 (stratified by FGF amplification [FGFR1, FGFR2, or FGF3] and presence of visceral disease) to receive intramuscular fulvestrant (500 mg q4w [with an additional dose 2 weeks after the initial dose]) in combination with oral dovitinib (500 mg, 5 days on/2 days off) or matching placebo until disease progression, unacceptable toxicity, death, or discontinuation (any reason). Crossover is not permitted. Eligibility criteria: Postmenopausal women with HER2-/HR+ breast cancer (N = 150) progressing within 12 months of completion of adjuvant endocrine therapy or after ≤ 1 prior endocrine therapy in the advanced setting are eligible. Other key inclusion criteria are: ECOG performance status ≤1; and adequate bone marrow and organ function; measurable disease as per RECIST 1.1 or ≥ 1 nonmeasurable lytic or mixed bone lesions in the absence of measurable disease. Patients with current or past evidence of CNS or leptomeningeal metastases, HER2 overexpression, and those who received previous treatment with fulvestrant or FGFR inhibitors are excluded. Specific aims: The primary endpoint is progression free survival (central review). Secondary endpoints include overall response rate, duration of response, overall survival, time to deterioration of ECOG performance status, patient-reported outcome scores, safety, and assessment of plasma pharmacokinetic concentrations of fulvestrant and dovitinib. Additionally, the pharmacodynamics of dovitinib on FGFR-associated angiogenic pathways and potential predictive biomarkers of response will be explored. Statistical methods: Analysis of primary endpoint will be carried out in FGF amplified subpopulation, FGF non-amplified subpopulation and the full population, using Bayesian methodology. Target accrual: Enrollment is ongoing. Target accrual is 150 patients (90 FGF amplified patients and 60 FGF non-amplified patients). Contact: For further information about the study please contact Gogov Sven (sven.gogov@novartis.com)/ Stephanie Deudon (stephanie.deudon@novartis.com). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-04.

T-DM1 Aids Patients with Advanced Breast Cancer

Abstract Genentech's antibody–drug conjugate T-DM1 improved progression-free survival in heavily pretreated breast cancer patients with advanced HER2-positive disease, in the phase III TH3RESA trial.

Efficacy and safety of metronomic capecitabine and gefitinib in heavily pretreated metastatic triple-negative breast cancer.

1071 Background: Metronomic chemotherapy regimens have shown efficacy in patients with metastatic breast cancer by antiangiogenic mechanisms. When used metronomically the toxicity profile of capecitabine is low. Triple negative breast cancer is a common problem in India and developing countries. Approximately 30% of triple negative breast cancer express EGFR and its mutation. Methods: Since October 2003 to December 2011 we objectively tested response rates, clinical benefit, and safety of gefitinib and capecitabine administered with a metronomic schedule of 500 mg thrice daily in heavily pretreated metastatic breast cancer patients with gefitinib 250 mg once daily. 300 patients were screened for EGFR expression. Among 85 enrolled patients with EGFR positivity, 76 were evaluable. ECOG performance status (PS) was 0-2, median age 52 years (range 36-65), bone plus visceral metastasis in 40% of patients. Rest had only visceral metastasis. All the patients were pretreated with anthracyclines and taxanes. The combination was administered for a median duration of 32 weeks (range 12-166). Results: We observed 18 partial responses (PR: 24%), 42 (55%) stable disease (SD). Median time to progression was 53 weeks, (95% CI, range 12-166 weeks). Safety of metronomic capecitabine with gefitinib was excellent. Neither grade 2-4 haematological or clinical side effects were recorded. Only 12 patients experienced grade I (WHO) hand-foot syndrome. Conclusions: Treatment with metronomic capecitabine and gefitinib was effective and minimally toxic in heavily pretreated breast cancer patients.

A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with capecitabine for advanced solid tumors (including patients with progressive or recurrent HER2-negative metastatic breast cancer).

3057 Background: CD105 (endoglin) is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels that is essential for angiogenesis and upregulated by hypoxia and VEGF inhibition. TRC105 is an anti-CD105 monoclonal antibody being studied in phase II trials that potentiates chemotherapy in preclinical models. Methods: Pts with advanced solid tumors (for purposes of dose escalation) or pts with metastatic HER2-negative breast cancer (following completion of dose escalation), ECOG PS 0-1, and normal organ function were treated with intravenously administered TRC105 wkly plus capecitabine at 1,000 mg/m2 BID for 14 of every 21 days, and assessed for safety, PK, and response. Results: Fourteen patients (median age = 52; M:F 4:10; median of 3 prior regimens; 10 with breast and 4 with colorectal cancer) were enrolled. Dose escalation proceeded from 7.5 mg/kg TRC105 to the recommended single agent phase II dose of 10 mg/kg of TRC105 in combination with capecitabine, without development of dose limiting toxicity. Fourteen pts were treated at 7.5 mg/kg (n=4) or 10 mg/kg (n=10) TRC105 wkly + 1,000 mg/m2 BID/14d capecitabine of repeating 21 day cycles. Patients experienced expected TRC105 related adverse events of grade 1 or grade 2 infusion reaction, epistaxis, gingival bleeding, telangiectasia, headache, rash, and fatigue. Grade 3 headache and grade 3 vomiting were each seen in one patient. Adverse events characteristic of each individual drug were not increased in frequency or severity when the two drugs were administered together. Mucocutaneous telangiectasia, a marker of TRC105 target modulation, was observed at both dose levels. A heavily pretreated male breast cancer patient remained on study for 9 months with a RECIST-defined partial response. Stable disease beyond 9 weeks was observed in three patients. Conclusions: The recommended single agent phase II dose of 10 mg/kg TRC105 wkly was well tolerated in combination with capecitabine. The combination treatment could be advanced in HER2-negative breast or colorectal cancer. Clinical trial information: NCT01326481.

Safety and efficacy of metronomic non-pegylated liposomal encapsulated doxorubicin in heavily pretreated advanced breast cancer patients

Metronomic administration of the same chemotherapy agents (lower doses with closer intervals) may optimize their antiangiogenic properties. The aim of our study was to determine the efficacy and safety of a metronomic regimen based in non-pegylated liposomal doxorubicin (NPLD) in advanced breast cancer patients. Clinical records of patients with pretreated advanced breast cancer and who were treated with the Metronomic-Cooper-type regimen consisting of weekly fixed doses of NPLD (30 mg IV) plus 5-Fluorouracil (5-FU) (500 mg IV) plus vincristine (0.25 mg IV) and daily oral cyclophosphamide (50 mg) plus prednisone (20 mg) were reviewed. In 84 pretreated patients, a tumor response was observed in 38 patients (45 %); stable disease was observed in 23 patients (27 %). Median progression-free survival (PFS) time to progression was 8.4 months and median overall survival (OS) was 21 months. The most common grade 2-3 hematologic adverse event was neutropenia, which was observed in 47 patients (56 %). Febrile neutropenia was observed in 10 patients (12 %). The most common non-hematologic adverse events were asthenia and mucositis which were observed in 60 patients (71 %) and 26 patients (31 %), respectively. Three patients (4 %) experienced an asymptomatic decline of the left ventricular ejection fraction. NPLD-based metronomic regimen was effective and safe in pretreated advanced breast cancer patients. It could be considered as an appealing option to treat patients previously exposed to anthracyclines.