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(Background) Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) improve the prognosis of hormone receptor-positive HER2-negative breast cancer (HR+/HER2- BC) by approximately 5 years. However, some patients show resistance to CDK4/6i and have poor prognosis. Thus, predicting resistance in patients is important. Although PAM50 is a strong tool for predicting late recurrence risk in HR+/HER2- BC by analyzing gene expression signatures, it is not always available. The non-luminal disease score (NOLUS), developed as an approximate formula for PAM50, is a pathology-based subtyping assay used to predict non-luminal disease using immunohistochemical analysis (Pascual et al. Front Oncol, 2021). (Materials & Methods) This multicenter, retrospective observational study was approved by the central ethics committee of Gifu University. From December 2017 to December 2021, real-world data of patients with metastatic HR+/HER2- BC who received CDK4/6i therapy were collected from 11 institutes in Japan. Data were obtained for patients who received CDK4/6i, such as palbociclib (PAL) or abemaciclib (ABE), as the first- or second-line endocrine therapy. The association between the efficacy of CDK4/6i and NOLUS was investigated by evaluating pathological and clinical data, including progression-free survival (PFS) and overall survival (OS). Pathological data, including the expression levels of ER, PgR, HER2, and Ki67, were evaluated according to the ASCO/CAP guidelines by experienced pathologists in each institute using either primary or metastatic tumors. PFS was defined as the period from the 1) starting date of combination therapy to progressive disease (PD); 2) the starting date of combination therapy to PD when CDK4/6i was interrupted due to adverse events or patients’ preference; and 3) the starting date of endocrine monotherapy to PD when CDK4/6i was added. NOLUS was calculated using the formula: NOLUS (0-100) = -0.45*ER% − 0.28*PR% + 0.27*Ki67% + 73, and the patients were divided into two groups, NOLUS(+) [≥ 51.38, non-luminal disease] and NOLUS(−) [< 51.38, luminal disease]. The expression levels of ER, PgR, HER2, and Ki67 in each group were compared using Wilcoxon rank-sum and Fisher’s exact tests. Next, prognosis, including survival rate, PFS, and OS, was evaluated with a 95% confidence interval (CI) using the Kaplan–Meier method with the log-rank test. Statistical significance was set at p < 0.05. (Results) Of the 300 patients, 28 (9.3%) were NOLUS(+) and 272 (90.7%) were NOLUS(−). The expression rates (%) in NOLUS(+) and NOLUS(−) were, respectively, 28.2 ± 19.4 and 89.0 ± 11.3 for ER (p < 0.001); 6.3 ± 15.9 and 44.3 ± 37.9 for PgR (p < 0.001); and 42.5 ± 23.8 and 26.9 ± 19.1 for Ki67 (p < 0.001). The expressions of HER2 (score 0, 1, 2, and ISH-negative, 3) were 42.9%, 28.6%, 28.6%, and 0% for NOLUS(+); and 30.8%, 51.7%, 17.5%, and 0.4% for NOLUS(−) (p = 0.086). There were apparent statistical differences in prognosis between the NOLUS(+) and NOLUS(−) groups. PFSs for 6M and 1y were 71.4% and 30.5% for NOLUS(+), and 85.2% and 66.6% for NOLUS(−) (HR, 3.15; 95%CI: 2.02-4.93; p < 0.001). OS for 6M and 1y were 92.6% and 92.6% for NOLUS(+), and 97.7% and 93.8% for NOLUS(−) (HR, 3.01; 95%CI: 1.48-6.09, p = 0.001). NOLUS(−) patients showed statistically better PFS with first-line therapy than with second-line therapy. However, NOLUS(+) patients showed no prognostic difference between the first and second therapeutic lines, suggesting CDK4/6i inefficacy. (Conclusion) CDK4/6i efficacy and prognosis were significantly different between NOLUS(+) and NOLUS(−) patients. This feasible method can predict patients with CDK4/6i-resistance and help select a better therapeutic approach to overcome resistance. Citation Format: Manabu Futamura, Takahiro Nakayama, Tersuhiro Yoshinami, Chiya Oshiro, Mikiya Ishihara, Midori Morita, Akira Watanabe, Azusa Taniguchi, Masami Tsukabe, Masafumi Shimoda, Kanae Mitta, Yoko Chihara, Hiroyuki Yasojima, Yoshimi Ouchi, Yoshihisa Tokumaru, Takuma Ishihara, Norikazu Masuda. Detection of high-risk patients resistant to CDK4/6 inhibitors with hormone receptor-positive HER2-negative breast cancer in Japan [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-05.

Background Pegfilgrastim (PEG) is a sustained-duration pegylated form of filgrastim, a granulocyte-colony stimulating factor agent that is widely used as prophylaxis against febrile neutropenia during chemotherapy. We report the case of a breast cancer patient who developed PEG-induced vasculitis complicated by subarachnoid hemorrhage (SAH) and review the relevant literature. Case presentation A 48-year-old woman had undergone surgery for breast cancer and was receiving docetaxel and cyclophosphamide as adjuvant chemotherapy (docetaxel 75 mg/m2, cyclophosphamide 600 mg/m2); on day 4 of treatment, PEG had been administered. On day 14, she was admitted to hospital with fever, general malaise, and neck pain, and her C-reactive protein level was found to be high (12.65 mg/dL). Although infection was initially suspected, antimicrobial treatment was ineffective and other laboratory test results were negative for this. Contrast-enhanced computed tomography on day 22 showed thickened vessel walls in the left subclavian artery, the origin of the common carotid artery, and the thoracoabdominal aorta. On day 26, magnetic resonance imaging of the head to investigate possible causes of headache showed signs consistent with SAH, and magnetic resonance angiography images showed irregularity in the basilar artery wall; the findings of both studies were considered to be due to PEG-induced vasculitis. Once treatment with prednisolone 40 mg/day had started, the wall thickening and irregularity improved. Conclusion Although an uncommon adverse effect, vasculitis affecting vessels of various sizes may be caused by PEG. To the best of our knowledge, this report is the first to describe a case of G-CSF-induced vasculitis complicated by SAH. In cases of persistent high fever and elevated inflammatory response after PEG administration and in the absence of infection, clinicians should consider the possibility of drug-induced vasculitis.