Abstract 5203: Identification of prognostic and predictive biomarkers for palbociclib add-on therapy using cancer panel sequencing of cell-free DNA in patients with HR-positive HER2-negative advanced and metastatic breast cancer with fulvestrant resistance
Authors: Takeshita Takashi , Iwamoto Takayuki , Niikura Naoki , Watanabe Kenichi , Kikawa Yuichiro , Kobayashi Kokoro , Iwakuma Nobutaka , Okamura Takuho , Tada Hiroshi , Ozaki Shinji , Okuno Toshitaka , Toh Uhi , Yamamoto Yutaka , Tsuneizumi Michiko , Ishiguro Hiroshi , Masuda Norikazu , Saji Shigehira 
Published: March 2024

Abstract
Purpose: The combination of cyclin-dependent kinase 4/6 inhibitors with endocrine therapies has shown promise for improving the survival of patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced and metastatic breast cancer (ABC/MBC). The FUTURE trial (UMIN000029294) demonstrated that adding palbociclib after acquiring fulvestrant resistance is potentially safe and effective. To further identify biomarkers for patient selection, this preplanned translational sub-study aims to use cancer panel sequencing of cell-free DNA (cfDNA) to discover prognostic and predictive biomarkers for additional palbociclib treatment after acquiring fulvestrant resistance in patents with HR-positive/HER2-negative ABC/MBC.
Methods: Herein, we utilized 149 cfDNA samples from 61 patients with disease progression after fulvestrant monotherapy and who subsequently received fulvestrant and palbociclib. Circulating cfDNA was analyzed at the time of palbociclib addition after fulvestrant resistance, on day 15 of cycle one (D15), and at the end of treatment (EOT) using the ThruPLEX ctDNA Assay, which can identify single or multi nucleotide variants, DNA insertions, and deletions in up to 34 cancer-associated genes.
Results: The genetic landscape of patients with BC undergoing palbociclib treatment was dynamic and changed over the course of treatment. Regarding progression-free survival, alterations in NRAS (Hazard Ratio (HR): 11.97, P &lt; 0.005)), MAP3K1 (HR: 6.86, P &lt; 0.005), and TP53 (HR: 3.6, P = 0.02) were identified in cfDNA on D15 and were linked to poor prognoses. Alterations in CBFB at baseline (HR: 5.15, P = 0.01), in BRCA2 (HR: 7.17, P &lt; 0.005) and NRAS (HR: 5.32, P &lt; 0.005) at D15, and ESR1 (HR: 4.37, P = 0.01) at EOT were also linked to poor prognosis, whereas alterations in WEE1 (HR: -5.84, P = 0.02) at EOT were associated with a favorable prognosis. Alterations in ESR1, WEE1, CBFB, and BRCA2 were prognostic factors at peak frequencies during treatment. Moreover, our research uncovered a novel observation that as treatment progressed, the relationship between prognostic factors focused on alterations in ESR1 and TP53 tended to weaken.
Conclusion: Cancer panel testing for cfDNA identified prognostic and predictive biomarkers for palbociclib add-on therapy after acquiring fulvestrant resistance in patients with HR-positive/HER2-negative ABC/MBC. These findings have important implications for patient selection and personalized treatment strategies in such patients.
Citation Format: Takashi Takeshita, Takayuki Iwamoto, Naoki Niikura, Kenichi Watanabe, Yuichiro Kikawa, Kokoro Kobayashi, Nobutaka Iwakuma, Takuho Okamura, Hiroshi Tada, Shinji Ozaki, Toshitaka Okuno, Uhi Toh, Yutaka Yamamoto, Michiko Tsuneizumi, Hiroshi Ishiguro, Norikazu Masuda, Shigehira Saji. Identification of prognostic and predictive biomarkers for palbociclib add-on therapy using cancer panel sequencing of cell-free DNA in patients with HR-positive HER2-negative advanced and metastatic breast cancer with fulvestrant resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5203.