Abstract PO1-13-02: Circulating tumor DNA mutation landscape in HR+/HER2− patients with mBC treated with cyclin-dependent kinase 4/6 inhibitors in the SCRUM-Japan MONSTAR-SCREEN study
Authors: Hattori Masaya , Serelli-Lee Victoria , Naito Yoichi , Yamanaka Takashi , Yasojima Hiroyuki , Nakamura Rikiya , Fujisawa Takao , Imai Mitsuho , Nakamura Yoshiaki , Bando Hideaki , Kawaguchi Tsutomu , Yoshino Takayuki , Iwata Hiroji 
Published: May 2024

Introduction: Combination of cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6i) + endocrine therapy (ET) is recommended as first- or second-line treatment (1L or 2L Tx) for hormone receptor-positive, human epidermal growth factor receptor-2-negative metastatic breast cancer (HR+/HER2− mBC). In this study, we assessed cancer-specific genetic alterations in circulating tumor DNA (ctDNA) and tissues in abemaciclib-treated patients with HR+/HER2− mBC in Japan.

Methods: MONSTAR-SCREEN is a multicenter study and part of a nation-wide cancer genome screening project for patients with advanced solid tumors (SCRUM Japan). Regardless of the Tx line, the current analysis included abemaciclib-treated patients with HR+/HER2− mBC (N=97). Data were collected between Jan 2020 and Dec 2021. Blood samples collected at ≤21 days before abemaciclib initiation (baseline; n=77) and at disease progression or Tx discontinuation (paired post-Tx; n=33) were tested with the FoundationOne® Liquid Companion Diagnostic panel. Additionally, archival or fresh tissue biopsy samples (n=79) were tested with the FoundationOne® Companion Diagnostic panel. Patient characteristics, baseline genetic alterations, neoplastic burden (measured by shedding rate and maximum variant allele frequency [VAF]), and alterations at clinical progression were reported.

Results: The total population (N=97) included patients with next generation sequencing ctDNA and/or tissue data. All were female with median age of 57 years (interquartile range 50, 67). Bone, either alone or with other sites, was the most common metastatic site (61%). 78% of patients received abemaciclib in the first or second line of Tx (LoT). Fulvestrant with or without gonadotropin-releasing hormone (55%), letrozole (24%), and anastrozole (11%) were the most common concomitant drugs. Among patients with baseline ctDNA data (n=77), 30% and 21% had received prior ET and prior chemotherapy, respectively. In baseline ctDNA samples, PIK3CA (37%) and TP53 (28%) alterations were detected most frequently across all LoT; while ESR1 (16%), GATA3 (11%), and FGF3/4/19 (9%) were more frequently detected in samples from later LoT. The frequency of ESR1 alterations (p&lt; 0.01), shedding rate, and maximum VAF (both p&lt; 0.05) were significantly higher in prior ET recipients than those who did not receive prior ET. Frequency of post-Tx ESR1 alterations numerically decreased from baseline in patients on fulvestrant (23% to 18%) and numerically increased in patients on aromatase inhibitors (27% to 45%). Other genes showed either a numeric increase or similar alteration frequency between the baseline and post-tx. Newly acquired post-Tx alterations were detected in FGF3/4/19 (18%); PIK3CA, TP53, and RB1 (all 15%) and ESR1 (12%). The table shows PIK3CA and ESR1 alterations detected at baseline and post-Tx. In the tissue samples (n=79), TP53 (32% vs 20%) and ESR1 (14% vs 7%) alterations were numerically more frequent in metastatic versus primary lesions. Other gene alteration frequencies were similar.

Conclusion: PIK3CA alterations were the most frequently detected genetic alterations in both pre- and post- abemaciclib Tx patients with HR+/HER2− mBC. Patients with prior ET had more frequent ESR1 alterations and higher neoplastic burden. Evidence from this study provides insight into the ctDNA dynamics and potential resistance mechanisms in patients with HR+/HER2− mBC.

PIK3CA and ESR1 alterations detected in circulating tumor DNA at baseline and post abemaciclib treatment

Citation Format: Masaya Hattori, Victoria Serelli-Lee, Yoichi Naito, Takashi Yamanaka, Hiroyuki Yasojima, Rikiya Nakamura, Takao Fujisawa, Mitsuho Imai, Yoshiaki Nakamura, Hideaki Bando, Tsutomu Kawaguchi, Takayuki Yoshino, Hiroji Iwata. Circulating tumor DNA mutation landscape in HR+/HER2− patients with mBC treated with cyclin-dependent kinase 4/6 inhibitors in the SCRUM-Japan MONSTAR-SCREEN study [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 PO1-13-02.