Real-World Predictors of Severe Neutropenia Associated with Palbociclib and Endocrine Therapy for Metastatic Breast Cancer in Japanese Patients.

Therapy for patients of metastatic breast cancer based on palbociclib, a cyclin-dependent kinase 4/6 inhibitor, has been approved in Japan. However, the risk factors for palbociclib-induced severe neutropenia in Japanese patients are rarely reported. Hence, the present study is aimed to identify the risk factors for adverse events requiring palbociclib dose reduction or discontinuation, and to identify the factors necessary to identify a more stable strategy for treatment continuation. This retrospective cohort analysis included patients with advanced breast cancer treated with 125 mg/d palbociclib. We demonstrated that severe neutropenia required significant dose reduction or therapy cessation. Most (77%) of the patients had severe neutropenia within the three courses. Risk factors for grade 3 or higher included low neutrophil counts (< 3250 /µL) before treatment [odds ratio (OR) = 9.10, 95% confidence interval (CI) (2.80-29.41), p < 0.001] and high age-adjusted Charlson comorbidity index (> 9) [OR = 1.64, 95% CI (1.09-2.48), p = 0.018]. Thus, low baseline neutrophil counts and high values for Age-adjusted Charlson comorbidity index are prospective predictive markers for palbociclib-induced severe neutropenia.

Clinical Management of Potential Toxicity of Abemaciclib and Approaches to Ensure Treatment Continuation.

INTRODUCTION: The association between abemaciclib dose reduction and treatment adherence is not clear. In this study, we examined real-world data of Japanese patients with advanced breast cancer (ABC) to determine how abemaciclib dose reduction is related to treatment continuation. METHODS: This retrospective observational study involved 120 consecutive patients with ABC who received abemaciclib from December 2018 to March 2021. The time to treatment failure (TTF) was estimated using the Kaplan-Meier method. Univariate and multivariate analyses were performed to identify factors associated with a TTF of >365 days (TTF365). RESULTS: According to the dose reduction during treatment, the patients were classified into 100, 200, and 300 mg/day abemaciclib groups. The 300 mg/day group had a TTF of 7.4 months, whereas the 100 and 200 mg/day groups had significantly longer TTFs (17.9 and 17.3 months, respectively; P = 0.0002). In this study, relative to the 300 mg/day arm, TTF was improved in 200mg/day arm and 100 mg/day arm (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.33-0.93) and [HR], 0.37; 95% CI, 0.19-0.74). For patients who received 300mg/day of abemaciclib dose arm, 200mg/day, and 100mg/day, the median TTF was 7.4 ,17.9 and 17.3 months. The frequently reported adverse effects (AEs) were anemia, increased blood creatinine levels, diarrhea, and neutropenia (90%, 83%, 83%, and 75% of the patients, respectively). Neutropenia, fatigue, and diarrhea were the top AEs causing dose reduction. A multivariate analysis that examined factors associated with achieving TTF 365 confirmed that dose down was an important factor (odds ratio: 3.95, 95% confidence interval: 1.68-9.36, P = 0.002). CONCLUSIONS: In this study, the 100 and 200 mg/day groups had a longer TTF than the 300 mg/day group, and dose reduction was identified as an important factor in achieving longer TTF.

Programmed death ligand 1-positive immune cells in primary tumor or metastatic axillary lymph nodes can predict prognosis of triple-negative breast cancer even when present at < 1% in the tumor region.

BACKGROUND: The efficacy of pre-operative systemic treatment (PST) combined with immune checkpoint inhibition (ICI) for triple-negative breast cancer (TNBC) has been recognized recently as being independent of the degree of programmed death ligand-1 (PD-L1) positivity of infiltrating immune cells, especially for patients with axillary lymph node metastasis (ALNM). METHODS: TNBC patients with ALNM were treated surgically between 2002 and 2016 in our facility (n = 109), of whom 38 received PST before resection. The presence of tumor-infiltrating lymphocytes (TILs) expressing CD3, CD8, CD68, PD-L1 (detected by antibody SP142) and FOXP3 at primary and metastatic LN sites was quantified. RESULTS: The size of invasive tumor and the number of metastatic axillary LN were confirmed as prognostic markers. The numbers of both CD8+ and FOXP3+ TILs at primary sites were also recognized as prognostic markers, especially for overall survival (OS) (CD8, p = 0.026; FOXP3, p < 0.001). The presence of CD8+, FOXP3+ and PD-L1+ cells was better maintained in LN after PST and may contribute to improved antitumor immunity. Provided they were present as clusters of ≥ 70 positive cells, even < 1% of immune cells expressing PD-L1 at primary sites predicted a more favorable prognosis for both disease-free survival (DFS) (p = 0.004) and OS (p = 0.020). This was the case not only for 30 matched surgical patients, but also in all 71 surgical only patients (DFS: p < 0.001 and OS: p = 0.002). CONCLUSIONS: PD-L1+ , CD8+ or FOXP3+ immune cells in the tumor microenvironment (TME) at both primary and metastatic sites are significant on prognosis, which could be a clue to expect the potential for better responses to the combination of chemotherapy and ICI, especially for patients with ALNM.

Significance of prostate/pancreatic/skin cancer family history for detecting BRCA2 pathogenic variant careers among patients with breast cancer.

BACKGROUND: When considering BRCA1/2 genetic testing for diagnosis of hereditary breast and ovarian cancer (HBOC), family history (FH) of breast and ovarian cancer is commonly considered. However, FH of other HBOC-related cancers, such as prostate, pancreatic, and skin cancer (malignant melanoma), is often overlooked. METHODS: Among 945 patients who received genetic testing of BRCA1/2 at our hospital between October 2010 and September 2021, we compared the FH of 123 patients diagnosed with HBOC and 669 other patients who had breast cancer and had a documented FH. This study focused on the FH of HBOC-related cancers such as breast, ovarian, prostate, pancreatic, and skin cancer, as well as colorectal, gastric, liver, lung, and uterine cancers, which are common among Japanese, and other cancers. RESULTS: FH of prostate, pancreatic, and skin cancer was significantly higher in the BRCA2 pathogenic variant (PV) cases than in the wild-type (WT) cases. The mean number of family members are as follows: BRCA1 PV/ BRCA2 PV/ WT; prostate cancer: 0.05/ 0.34/ 0.09 (P < 0.0001, Kruskal-Wallis multiple comparisons test), pancreatic cancer: 0.13/ 0.21/ 0.10 (P = 0.01637), and skin cancer: 0.03/ 0.07/ 0.01 (P = 0.00129), respectively. CONCLUSIONS: When considering BRCA1/2 genetic testing, FH of prostate, pancreatic, and skin cancers may also be examined as HBOC-related cancers to provide testing for patients who would benefit from it. However, further studies for the association between skin cancer and HBOC will be required because it has not been reported in Japan.