Letter to the Editor: Revisiting the anatomical pattern of bone metastases in stage IV breast cancer: Missing clinical stratification and biological depth

Abstract

The recent article by Zari et al published in World Journal of Clinical Oncology on bone metastases patterns in stage IV breast cancer offers valuable insight by stratifying anatomical distribution according to histological subtypes. However, some important clinical and biological aspects remain insufficiently addressed. For instance, the lack of data on diagnostic imaging methods, prior systemic therapies, and metastatic burden limits the interpretation of survival outcomes. Moreover, the prognostic implications of specific skeletal sites, such as spinal vs appendicular involvement are not fully discussed. We believe that integrating anatomical findings with clinical history and biological markers would offer a more complete understanding and greater translational value.

Key Words: Imaging; Human epidermal growth factor receptor 2; Hormone receptor; Molecular subtypes; Bone metastases; Breast cancer

Core Tip: This letter highlights several overlooked aspects in a recent study on bone metastases in breast cancer, including the absence of molecular subtype stratification, survival outcomes, and lesion-level anatomical detail. We argue that incorporating imaging approaches, clinical context, and biomarker profiles is essential to make such anatomical findings more clinically meaningful and translatable.

TO THE EDITOR

We read with great interest the study by Zari et al[1] published in World Journal of Clinical Oncology, titled “Anatomical distribution of bone metastases in stage IV breast cancer: According to histological subtype”. The aim of this letter is to contextualize their anatomical findings within the broader landscape of molecular subtyping, clinical heterogeneity, and emerging imaging and analytic approaches, and to outline several considerations that may further enhance the clinical relevance of their work. This work represents a valuable effort to anatomically map skeletal metastatic patterns across common histologic subtypes, drawing attention to the spatial tropism of bone metastases, a topic often underexplored in clinical literature. By providing site-specific distribution data, the authors offer useful descriptive insights that may help guide initial imaging or palliative decision-making in advanced breast cancer.

Bone remains the most frequent site of distant spread in breast cancer, affecting approximately 60%-80% of metastatic cases, particularly in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) tumors[2]. Prior population-based studies have shown that bone involvement is often the first site of distant relapse, with median survival ranging from 60 months to 72 months for bone-only disease, though long-term survival remains limited[3]. While the imaging-based findings from Zari et al[1] are informative, several limitations in design, analysis, and clinical contextualization merit further consideration.

Lack of molecular subtype integration

Although patients were stratified by histological subtype (e.g., invasive ductal carcinoma, invasive lobular carcinoma), the study did not incorporate intrinsic molecular subtypes (HR+/HER2-, HER2+, triple-negative). Prior studies have consistently shown that HR+/HER2- tumors preferentially metastasize to bone, whereas HER2+ and triple-negative breast cancer subtypes are more likely to involve visceral or central nervous system sites[2,4]. For example, estrogen receptor positive (ER+) tumors may exhibit bone metastasis rates exceeding 80%, whereas ER-negative (ER-) tumors can fall below 50%, reflecting distinct metastatic programming shaped by underlying molecular biology. Additionally, data from large registries indicate that metastatic invasive lobular carcinoma is more often associated with bone-only disease than invasive ductal carcinoma (24.2% vs 15.5%), and tends to confer more favorable survival outcomes[5]. Relatedly, solitary bone metastasis is associated with substantially longer survival than oligometastatic or multiple-site bone disease (mean survival 9.2 years vs 5.5 years)[6]. These nuances emphasize the value of integrating molecular classification and metastatic burden into analyses of skeletal dissemination patterns.

Clinical heterogeneity and missing prognostic correlates

The cohort appears to include patients undergoing initial staging for suspected breast cancer, yet the authors do not clarify imaging modalities used (18F-fluorodeoxyglucose positron emission tomography/computed tomography vs bone scintigraphy), systemic treatment history, or the extent of disease burden (e.g., number of lesions, visceral involvement). This limits the interpretability of lesion detection and survival associations. Notably, traditional bone scans have limited sensitivity (approximately 67%), particularly for small-volume disease, whereas positron emission tomography/computed tomography offers greater resolution at the cost of increased radiation exposure. Bone only metastasis represents a clinically distinct entity. In a recent cohort, the 2 years overall survival reached 93% for patients with bone-only disease, while it dropped to 69.5% in those with additional visceral metastases. Furthermore, among patients who developed skeletal-related events, particularly symptomatic fractures, the median survival declined substantially to approximately 7 months[7]. These outcome-based distinctions, particularly survival by anatomical site (e.g., pelvis vs spine vs extremities) were not addressed in the current study but could have strengthened its clinical relevance.

Statistical rigor and spatial resolution

The study relied primarily on descriptive statistics and did not adjust for potential confounders such as age, menopausal status, tumor size, or nodal stage. Prior Surveillance, Epidemiology, and End Results based models have identified multiple clinicopathological factors, including ER/progesterone receptor/HER2 status, T and N stage, tumor grade, and presence of visceral metastases, as independent predictors of bone metastasis[8]. Machine learning-based algorithms using such variables can predict bone involvement with high accuracy, revealing rates as high as 87% in ER+ tumors compared to < 56% in ER- ones[8]. Moreover, survival prediction models have incorporated variables such as therapy regimens, brain metastases, and marital status, yielding a 5 years overall survival estimate of approximately 22.8% for bone-metastatic breast cancer[9]. Anatomically, the vertebrae and pelvis represent the most commonly involved skeletal regions[3]. By aggregating vertebral subsegments or lumping less frequent sites into “other”, the authors may have obscured meaningful spatial patterns. Emerging radiomic techniques using three dimensions skeletal atlases and heatmaps could offer better lesion-level resolution and help unravel biologically driven tropisms.

CONCLUSION

Zari et al[1] published a study in World Journal of Clinical Oncology provide a useful anatomical snapshot of bone metastatic patterns in breast cancer, which may serve as a foundation for future spatial modeling or lesion-specific outcome studies. To maximize the translational value of such work, future studies should integrate anatomical mapping with intrinsic molecular subtypes, detailed clinical characteristics, and robust survival data, thereby enabling more personalized surveillance strategies and treatment planning for patients with bone-dominant metastatic breast cancer.