Abstract P2-08-04: Progressive metastatic breast cancer with no detectable circulating tumor DNA: Evaluating limitations of this highly sensitive tool
Authors: Shah Ami N , Gerratana Lorenzo , Chandra Shruti , Mukhija Dhruvika , Katam Neelima , Kang Anthony K , Davis Andrew A , Srivastava Millen , Jacob Saya , D'Amico Paolo , Zhang Qiang , Reduzzi Carolina , Gurley Michael , Wehbe Firas , Gradishar William J , Behdad Amir , Cristofanilli Massimo 
Published: March 2022

Abstract
Background: Circulating tumor DNA (ctDNA) is being evaluated as a tool to monitor disease and guide therapy escalation and de-escalation in advanced breast cancer. The patient, disease, and treatment characteristics that influence whether tumor DNA is isolated and sequenced from the bloodstream are not well understood. We aimed to describe patient and disease characteristics of cases with undetectable ctDNA levels despite progressive metastatic breast cancer (MBC). Methods: We retrospectively identified patients (pts) with MBC who had ctDNA evaluation by the Guardant 360 assay (Redwood City, CA) as part of their routine care from 2015-2020. We correlated the ctDNA assay with the disease status at collection. We identified the patient cohort with no detectable ctDNA despite evaluation at the time of progressive disease but prior to the initiation of a new therapy (ND ctDNA/PD) and compared the clinical, pathologic, and molecular features of this group to those with detected ctDNA. Differences were tested by two proportion z-tests. Results: Of 1151 ctDNA samples collected among 473 pts with MBC, 87 (7.5%) samples had no detectable (ND) ctDNA. 54 of 87 samples with ND ctDNA were collected at a time of stable or responding disease or after a new line of therapy was started, leaving only 33 ctDNA evaluations (2.8%) among 30 pts with ND ctDNA despite collection at the time of PD prior to new therapy. Among this group there were 14 pts (47%) with HR+ HER-, 11 pts (37%) with HER2+, and 5 pts (17%) with TN MBC. This compared to 254 pts (60%) with HR+ HER2-, 82 pts (19%) with HER2+, and 85 pts (20%) with TN MBC and detectable ctDNA. HER2-positive MBC was more common in the ND ctDNA/PD group than detectable ctDNA group (p-0.02). In the ND ctDNA/PD group, the median time from MBC diagnosis to ctDNA evaluation was 7 months and pts had received a median of 0.5 prior lines of therapy for MBC. Four pts (13%) had lobular breast cancer, 24 pts (80%) had recurrent disease, 14 pts (47%) had visceral metastases, and 12 pts (40%) had oligometastatic disease. Sites of metastases at the time of ND ctDNA/PD were bone n=16 (53%), lung n=7 (23%), liver n=6 (20%), lymph node n=11 (37%), skin and soft tissue n=5 (17%), and CNS n=5 (17%). When compared to those with detectable ctDNA these differences in characteristics were not statistically significant, although numerically pts with ND ctDNA had more CNS disease (17% vs 10%) and less liver disease (20% vs 32%). At the time of ND ctDNA, the site of progression was bone n=14 (47%), CNS n=5 (17%), lymph node n=9 (30%), lung n=7 (23%), and liver n=5 (17%). There was a single site of progression in 20 pts (67%). 16 of 30 pts had repeat ctDNA analysis of which 9 pts had subsequent detectable ctDNA with a median VAF of 0.3%, a median of 1 alteration per sample, and oncogenic or likely oncogenic alterations in TP53 in 3 pts and BRCA1, CCNE1, CDH1, and PIK3CA in 1 pt each. Seven had tissue NGS, all of which showed multiple oncogenic alterations. The remaining 22 pts with ND ctDNA but no PD were responding to therapy based on imaging or had already started a new therapy since the last progression. This group also had a high proportion of HER2+ MBC (n=7, 32%) and low proportion with visceral disease (n=6, 27%) Conclusions: Although ctDNA is a highly sensitive tool to detect active MBC (&lt;3% of samples had ND ctDNA), its sensitivity may be less in some clinical scenarios, including HER2+ MBC, when there are limited sites of progression, or when there is isolated CNS progression.
Citation Format: Ami N Shah, Lorenzo Gerratana, Shruti Chandra, Dhruvika Mukhija, Neelima Katam, Anthony K Kang, Andrew A Davis, Millen Srivastava, Saya Jacob, Paolo D'Amico, Qiang Zhang, Carolina Reduzzi, Michael Gurley, Firas Wehbe, William J Gradishar, Amir Behdad, Massimo Cristofanilli. Progressive metastatic breast cancer with no detectable circulating tumor DNA: Evaluating limitations of this highly sensitive tool [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-08-04.