Abstract P1-16-09: Low-dose chemotherapy (CT) + bevacizumab (Bev) combined with unchanged endocrine treatment (ET) in patients with recurrent luminal breast cancer progressing during ET – Effect determined by standard imaging and changes in ctDNA and CTC during treatment
Authors: Linderholm BK , Ekholm M , Wännstig A-K , Lundstedt D , Carlsson L , Tzikas A-K , Svensson J , Kristiansson H , Filges S , Ståhlberg A 
Published: May 2019

Background: Several mechanisms are involved in the development of endocrine resistance, such as mutations in the ESR1, PIK3CA, and TP53 genes and/or up-regulation of tyrosine kinase receptors such as the endothelial growth factor (VEGF) receptor. Preclinical data have revealed that sensitivity to endocrine therapy may be restored if these pathways are blocked.

Aims: To investigate the progression-free survival (PFS), overall response rate (ORR), and the toxicity of the study treatment. To use circulating tumor cells (CTC) and circulating tumor DNA (ct-DNA) at base-line and during treatment for next generation sequencing (NGS) to investigate whether changes in tumor mutations or in levels of CTC/ct-DNA correlate to treatment efficacy.

Patients and methods: Thirty-two patients aged 46-77 years with confirmed advanced breast cancer (ABC) progressing during ET were included. Treatment consisted of unchanged ET with the addition of cyclophosphamide 50mg x 1 and capecitabine 500mg x 3 daily + bevacizumab 15mg/kg iv. every third week (q21). Blood samples for analysis of CTC and ctDNA were collected at base-line, after the 1st and 2nd course, and at progression. CTC were isolated by use of an immune-magnetic selection (ADNA-test) and sequenced by NGS. ctDNA were analysed by the SiMSen-Seq (Simple Multiplexed PCR-based barcoding of DNA for Sensitive mutation detection using Sequencing) that allows mutant frequencies &lt; 0.1% to be detected.

Results: One patient did not start treatment and 2 were not evaluable. Palliative chemotherapy (1-2 lines) had been delivered before inclusion to 28% and &gt; 1 line of palliative ET to 58% of the patients. A total of 72% (n=21) of the patients had visceral disease (of whom 7 had liver metastases), and 28% (n=8) patients bone-only disease. Median PFS was 9.1 months (range 2.1-59.3 months). Best responses were: 1 patient (3%) received complete remission; 7 patients (24%) partial response; 16 patients (55%) SD (of whom 12 had CB, defined as SD &gt; 24 weeks), and 5 (17%) had progressive disease. The ORR (defined as CR, PR, or CB) was 69%. The most common toxicity was hypertension (62%), that resulted in termination in 2 patients, and 1 patient stopped treatment due to thrombocytopenia. Other side-effects were proteinuria grade 1-3 (24%); hand-foot-syndrome grade 1-2 (45%); mucositis grade 1 (14%); nausea grade 1 (14%) and diarrhea grade 1-3 (10%). CTC was isolated in 12 patients (37%). Three out of the 5 patients with PD at 12 weeks had detectable CTCs at base-line. Base-line ESR1, PIK3CA and TP53 mutations were found in CTC from 2 patients (17%), 7 patients (58%), and 5 patients (42%), respectively, but did not correlate to response.

Conclusion: The treatment was well tolerated with an ORR of 69%, which is considered very good in this setting. CTCs were only isolated in 37% of the patients which is comparable to previously reported results in metastatic luminal breast cancer and thus not a feasible method for monitoring treatment effect. Results on levels of consecutive ctDNA, as well as mutation pattern in relation treatment effect will be presented.

Citation Format: Linderholm BK, Ekholm M, Wännstig A-K, Lundstedt D, Carlsson L, Tzikas A-K, Svensson J, Kristiansson H, Filges S, Ståhlberg A. Low-dose chemotherapy (CT) + bevacizumab (Bev) combined with unchanged endocrine treatment (ET) in patients with recurrent luminal breast cancer progressing during ET – Effect determined by standard imaging and changes in ctDNA and CTC during treatment [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 P1-16-09.