Abstract P6-03-05: Cell-free DNA as molecular tool for monitoring disease progression and response to therapy in breast cancer patients
Authors: Liang DH , Patel A , Ensor JE , Patel TA , Chang JC , Rodriguez AA 
Published: May 2016

Abstract
Background: Identification of cancer-specific genes from breast cancer cells was instrumental in the advancement of targeted breast cancer therapy. However, with genomic heterogeneity within the breast cancer and evolution of cancer over time, genomic sequencing obtained from a single biopsy site may not capture the complete genomic profile. Thus, circulating cell-free DNA (cfDNA), isolated from plasma, is potentially a non-invasive source of identifying cancer-specific genomic alterations and may provide comprehensive genomic data throughout a patient's clinical course as they undergo anti-cancer therapy.
Method: We performed a retrospective chart review of 100 patients with stage 4 or high-risk stage 3 breast cancer who were tested for cfDNA genomic alterations. The most common actionable cancer specific genomic alterations were identified. In 23 patients who also had genomic analysis from tumor DNA (tDNA), an analysis using the Cohen's Kappa statistic was performed to determine the degree of agreement between genomic alterations found in tDNA and cfDNA. The proportion of patients with clinical disease progression between two cohorts determined by change in mutant allele frequency was compared using two-sided Fisher's exact test. Patients who received targeted therapy based on the identified genomic alteration were followed to determine response to therapy.
Results: In cfDNA of 100 breast cancer patients, the most commonly found cancer specific genomic alterations were TP53, PIK3CA, EGFR amplification, and ERBB2 amplification, with incidence rates 27%, 22%, 9%, and 7%, respectively. In tDNA of 23 patients, incidence rates were 65%, 26%, 9%, and 13%. PIK3CA and ERBB2 amplification demonstrated robust agreement between tDNA and cfDNA (Cohen's Kappa= 0.64 and 0.77, respectively). TP53 and EGFR amplification demonstrated poor agreement between tDNA and cfDNA (Cohen's Kappa= 0.18 and 0.33, respectively). There were 22 patients who had baseline and post-therapy mutant allele frequency measurements of TP53 and PIK3CA. Directional change of mutant allele frequency was closely associated with patient's response to therapy (p=0.0017). 8 out of 8 patients (100%) who had progression of disease had increase in mutant allele frequency. 10 out of 14 patients (71%) of patients who responded to therapy had decrease in mutant allele frequency. 6 patients who were found to have ERBB2 amplification were initiated on anti-HER2 cancer therapy. 5 of 6 patients (83%) had clinical response to therapy, while one patient had progression of disease. 3 patients who were found to have EGFR amplification (2 in cfDNA, 1 in tDNA) were initiated on anti-EGFR therapy. 2 of 3 patients (67%) had clinical response to therapy, while one patient had progression of disease.
Conclusion: There is no definite agreement between genomic alterations found in tDNA and those found in cfDNA. Whether this is due to tumor heterogeneity or tumor evolution over time with administration of anti-cancer treatment remains unknown. However, identification of selected cancer specific genomic alterations from cfDNA may be a non-invasive tool to monitor disease progression and response to breast cancer therapy.
Citation Format: Liang DH, Patel A, Ensor JE, Patel TA, Chang JC, Rodriguez AA. Cell-free DNA as molecular tool for monitoring disease progression and response to therapy in breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-03-05.