Distant metastasis of breast cancer is triggered by changes in the dynamics of metastatic cells after removal of the primary lesion

Abstract PURPOSE Breast cancer subtype influences the dynamics of distant recurrence. We investigated the timing of distant recurrence (distant disease-free interval DDFI) for each subtype and its relationship to stage, and perioperative treatment. PATIENTS AND METHODS We retrospectively analyzed data from 4,658 patients with stage I-III invasive breast cancer operated at Tokyo Metropolitan Komagome Hospital from 1998 to 2018. Patients were classified into five biological subtypes according to estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor 2 (HER2), and nuclear grade using immunohistochemistry findings: luminal A, luminal B/HER2-, luminal B/HER2+, HER2-enriched, Triple negative (TN). We investigated distant disease-free interval (DDFI) and analyzed the dynamics of distant metastasis. One-way analysis of variance was used to compare the recurrence patterns. RESULTS The median observation period was 6.3 years. Of the 4,051 patients for whom subtyping was possible, 422 developed distant recurrence. 5-year distant recurrence-free rates were 97.3% for luminal A, 86.8% for luminal B/HER2-, 89.1% for luminal B/HER2+, 84.6% for HER2-enriched, and 81 .7% for TN. In all subtypes, the recurrence rate increased with stage progression. The recurrence dynamics in luminal A showed a gradual peak at 3 years after starting treatment, after 5 years with more recurrences occurring than in other subtypes, especially late recurrences after 10 years. The median DDFI was 5.5 years (IQR 3.2-8.6 years). luminal B/HER2- and luminal B/HER2+ patients had similar recurrence dynamics, with peak recurrences at 2.4 and 2.3 years after starting treatment, respectively, followed by fewer recurrences over time, but recurrences were still observed after 5 years. Median DDFI was 3.1 years (IQR 1.9-5.9) and 2.9 years (IQR 1.9-5.9), respectively. HER2-enriched and TN showed similar recurrence dynamics, with a high peak of recurrence at 1.5 and 1.4 years, respectively, followed by a rapid decrease in recurrence and a rare recurrence after 5 years. The median DDFI was 1.8 years (IQR 1.1-2.5) and 1.6 years (IQR 1.1-2.9), respectively. When these recurrence dynamics were evaluated by stage for each subtype, the peak DDFI values for stage1, stage2, and stage3 were 3.4, 3.4, and 3.3 years for luminal A, 2.8, 2.7, and 2.1 years for luminal B/HER2-, 1.7, 2.2, and 2.6 years for luminal B/HER2+, 1.2,1.8, and 1.4 years for HER2-enriched, and 1.3,1.5, and 1.2 years for TN. There was no difference by stage for all subtypes (p=0.58, 0.25, 0.20, 0.74, and 0.26, respectively). Furthermore, the recurrence dynamics did not differ by the presence or absence of perioperative chemotherapy for each subtype (p=0.48, 0.31, 0.12, 0.34, and 0.09, respectively). Conclusion In all subtypes, distant metastasis incidence peaks between 1.5 and 3 years after surgery and then declines. The post-peak decline pattern showed characteristic dynamics for each subtype, but each peak in same subgroup was not associated with clinical stage or perioperative chemotherapy. Some kinds of the distant metastatic machinery may be caused by changes in the growth dynamics and microenvironment of distant cancer cells associated with primary tumor resection. Citation Format: Hiromi Tokisawa, Tomoyuki Aruga, Yayoi Honda, Toshiyuki Ishiba, Rika Yonekura, Naoko Iwamoto, Yuichi Kumaki. Distant metastasis of breast cancer is triggered by changes in the dynamics of metastatic cells after removal of the primary lesion [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 P4-07-25.