Breast cancer is a heterogeneous disease, and its subtypes are characterized by hormone receptor and human epidermal growth factor receptor 2 (HER2) expression status. “HER2-low” tumors, which exhibit a low level of HER2 expression (immunohistochemistry 1+ or 2+ without gene amplification), were conventionally considered not amenable to anti-HER2 targeting agents based on the results of a phase III trial of trastuzumab. However, this perspective is being challenged by the emergence of novel anti-HER2 antibody-drug conjugates, such as trastuzumab-deruxtecan. These innovative therapies have demonstrated remarkable efficacy against HER2-low breast cancer, shedding new light on a previously overlooked category of breast cancer. Such promising results highlight the need for in-depth investigations of the biology and prognostic implications of HER2-low tumors. In this review, we comprehensively summarize the current evidence surrounding this topic and highlight areas that warrant further exploration and research in the future.

The transition of human epidermal growth factor receptor 2 (HER2) status after neoadjuvant chemotherapy (NAC) in HER2-low breast cancer has not been thoroughly evaluated. Here, we evaluated the HER2 transition among HER2-zero and HER2-low breast cancer cases post-NAC and its impact on clinical outcomes. We included 1288 patients with HER2-low or zero breast cancer who underwent NAC and surgery between 2014 and 2018 and had paired pre- and post-therapeutic HER2 status results. Among patients who were HER2-zero pre-NAC (n = 650), 68% and 29% were HER2-zero and HER2-low, respectively, post-NAC. Among patients who were HER2-low pre-NAC (n = 638), 32% of patients showed HER2 changes (low to zero), and 59% of patients had a constant HER2-low status post-NAC. Patients with constant HER2-low or transitions from HER2-low to zero had a higher proportion of hormone receptor positivity (84% and 79%) than those with changes from HER2-zero to low (77%) or with constant HER2-zero (56%), respectively. Multivariable logistic regression analysis revealed that patients with oestrogen receptor positivity had a higher probability of gaining HER2-low expression than those with oestrogen receptor negativity (odds ratio 2.48). No significant differences were observed in terms of overall survival or disease-free survival between patients with and without HER2-changes according to their hormone receptor status, except in the post-therapeutic HER2-low, hormone receptor-negativity subset. Temporal heterogeneity of HER2-low expression is observed in substantial numbers of post-NAC breast cancer patients. Clinical outcomes show no significant associations, except in the post-therapeutic HER2-low, hormone receptor negativity subset. The prognostic implications of HER2 transition in HER2-low breast cancer require further investigation.

Antibody–drug conjugates (ADCs) offer a promising therapeutic approach for various cancers, enhancing the therapeutic window while mitigating systemic adverse effects on healthy tissues. ADCs have achieved remarkable clinical success, particularly in treating breast cancer, becoming a standard therapy across all subtypes, including hormone receptor-positive, human epidermal growth factor receptor 2-positive, and triple-negative breast cancer. Although designed to selectively target antigens via monoclonal antibodies, ADCs can exhibit toxicity in normal tissues, often due to off-target effects of their cytotoxic payloads. Understanding and managing these toxicities according to established guidelines are crucial for enhancing ADC clinical efficacy, minimizing adverse events, and ultimately improving patient outcomes. This review comprehensively examines the toxicities of ADCs employed in breast cancer treatment and explores their management strategies. Furthermore, we investigate novel ADCs beyond trastuzumab deruxtecan and sacituzumab govitecan, evaluating their potential efficacy and corresponding safety profiles.

Purpose Three years of adjuvant imatinib is the standard treatment for resected gastrointestinal stromal tumors (GISTs) with rupture, but the recurrence rate is prominently high. We aimed to investigate the efficacy and safety of 5-year adjuvant imatinib compared with 3-year treatment in patients with a ruptured GIST following surgical resection.Materials and Methods A total of 51 patients were included in the analysis. The assessment of GIST rupture was based on Nishida’s classification. Twenty patients who were diagnosed before November 2013 were treated with 5 years of imatinib, and 31 patients who were diagnosed after November 2013 were treated with 3 years of imatinib. We retrospectively compared the clinical outcomes of the two groups.Results Baseline characteristics and the incidence of the adverse events were generally comparable between the two groups. During a median follow-up duration of 43.8 months and 104.2 months in the 3- and 5-year group, 8 and 9 patients had a disease recurrence, respectively. The 5-year group showed better recurrence-free survival (RFS) than the 3-year group. In multivariate analysis, low mitotic index was a significant independent favorable prognostic factor for RFS, while 5-year imatinib treatment was marginally associated with a favorable RFS.Conclusion Five years of adjuvant imatinib treatment in patients with ruptured GIST was associated with favorable survival outcomes with manageable toxicity profiles. Our findings warrant validation and confirmation in future studies.

Purpose Prognostic Index for Natural Killer Lymphoma (PINK) is the most widely accepted prognostic model for patients withextranodal natural killer/T-cell lymphoma (ENKTL) treated with non-anthracycline–based therapy. We aimed to evaluate the prognostic implications of serum β-2 microglobulin (β2M) in the context of PINK and proposed a new prognostic model.Materials and Methods A total of 138 patients who were newly diagnosed with ENKTL and treated with non-anthracycline-based chemotherapy were identified. The cut-off value of high serum β2M was calculated by maximal-chi square methods (4.1 mg/L). A new prognostic model incorporating serum β2M into PINK was proposed and validated in an independent validation cohort (n=88).Results The patients’ median age was 53.5 years (range, 19 to 80 years). Patients with high serum β2M levels had significantly worse overall survival (OS) and progression-free survival (PFS). In multivariate analysis, high serum β2M was an independent adverse prognostic factor for OS. A new PINK-B (Prognostic Index for Natural Killer Lymphoma-serum β-2 microglobulin) model stratifiedpatients into three groups with distinct OS and PFS in the training cohort (3-year OS, 84.1% [95% confidence interval, 75.1 to 94.2], 46.8% [36.1 to 60.8] and 17.6% [6.3 to 49.2] for the low-, intermediate, and high-risk groups, respectively; 3-year PFS, 70.6% [59.4 to 83.8], 35.9% [25.9 to 49.8], and 7.35% [1.1 to 46.7] for the low-, intermediate-, and high-risk groups, respectively). The PINK-B model was further validated in an independent cohort.Conclusion Serum β2M is an independent prognostic factor for ENKTL patients. The new serum β2M-based prognostic model may be useful for identifying ultra-high-risk patients, and it can easily be adopted into daily clinical practice.