Evolutionary histories of breast cancer and related clones.

Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1-3. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.

Sentinel lymph node biopsy in extramammary Paget disease: A 13-year institutional experience.

Whether sentinel lymph node biopsy status is a prognostic factor or effective in determining treatment strategies in extramammary Paget disease remains unclear. This study aimed to investigate the significance of sentinel lymph node biopsy in extramammary Paget disease. We retrospectively reviewed the clinical information of previously untreated patients with invasive extramammary Paget disease who underwent wide local excision of the primary tumor and sentinel lymph node biopsy at our hospital between April 2008 and March 2021. Clinical data including the baseline neutrophil-to-lymphocyte ratio and recurrence-free survival were analyzed. Sentinel lymph node metastases were classified as macrometastases and micrometastases, with a cut-off value for sentinel lymph node tumor burden of 2 mm. Univariate and multivariate analyses of factors affecting sentinel lymph node biopsy positivity and recurrence-free survival rates were performed. Overall, 85 patients were included in the analysis. Patients in the sentinel lymph node biopsy-positive group (n = 26) had a significantly higher invasion level and neutrophil-to-lymphocyte ratio. According to multivariate analyses, invasion level and a high neutrophil-to-lymphocyte ratio were independent predictive factors for sentinel lymph node biopsy positivity, and the sentinel lymph node biopsy status was an independent prognostic factor for recurrence-free survival. In conclusion, sentinel lymph node biopsy provides an accurate risk classification and clinical indication for postoperative follow-up in patients with invasive extramammary Paget disease.

Neutrophil-to-lymphocyte ratio is a potential prognostic biomarker for extramammary Paget disease: A retrospective study.

The neutrophil-to-lymphocyte ratio (NLR) is a useful prognostic biomarker for many cancer types. However, the prognostic value of NLR in patients with extramammary Paget disease (EMPD) remains unclear. This study aimed to determine whether NLR is associated with overall survival (OS) in patients with EMPD. In this single-center retrospective case series, we analyzed data of 109 patients with previously untreated EMPD who presented to our hospital. Data on age, sex, primary tumor site, invasion level, presence of lymph node and distant metastases, baseline NLR, and OS were analyzed. The enrolled patients were classified into the metastatic or non-metastatic EMPD groups. The metastatic EMPD group had higher invasion level and NLR value (p < 0.001 and p = 0.005, respectively) compared with the non-metastatic EMPD group. Cox proportional hazards model analysis showed invasion level (p = 0.0093) and NLR value (p = 0.019) to be independent prognostic factors for OS. Notably, multivariate analysis revealed that invasion level (p = 0.045) and NLR value (p = 0.036) were independent prognostic factors for OS in the metastatic EMPD group. The limitations of this study include the small number of participants and its retrospective nature. In conclusion, since NLR can be routinely assessed with high feasibility, it might be a useful biomarker for predicting prognosis in patients with EMPD.

Neutrophil-to-lymphocyte ratio is associated with survival and sentinel lymph node positivity in invasive cutaneous squamous cell carcinoma: A retrospective study.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is a known prognostic biomarker for survival and is predictive of sentinel lymph node (SLN) positivity in some cancers. However, its usefulness as a prognostic biomarker for cutaneous squamous cell carcinoma (cSCC) has not been fully investigated. OBJECTIVE: Our objective was to investigate the relationship between the NLR and the disease-specific survival and SLN positivity in patients with cSCC. METHODS: In this single-center retrospective case series, we analyzed patients with cSCC who underwent blood tests prior to the initiation of treatment at our oncology hospital. The relationship between the patients' clinical characteristics (including the NLR) and the disease-specific survival and SLN positivity was evaluated using univariate and multivariate analyses. RESULTS: An elevated NLR was an independent prognostic factor for poor disease-specific survival and a predictive factor for SLN positivity. LIMITATIONS: Limitations include the small number of participants and selection bias due to the large proportion of high-risk cases in our patient population. CONCLUSION: NLR is a useful biomarker in cSCC because it is simple to measure and can predict prognosis.

Development of an easy method to test for HER2 in breast cancer using dual-color in situ hybridization.

BACKGROUND: Although human epidermal growth factor receptor 2 (HER2) is a significant clinical biomarker for breast cancer, the HER2 testing involves a complicated evaluation process. We devised an easy method for HER2 gene testing and investigated its utility. METHODS: HER2 testing was performed by immunohistochemistry (IHC) and dual-color in situ hybridization (DISH) on surgical specimens from 50 patients with invasive breast cancer. DISH was evaluated by two methods. One was the DISH count method in which the HER2 and CEP17 signals were counted and the HER2/CEP17 signal ratio was calculated. The other was the DISH-easy method in which pathologists only observed slices without counting the signals. The DISH-easy method was performed by two pathologists. We analyzed the correlations between the DISH-easy method and the DISH count method by each pathologist and calculated the inter-observer concordance rate of the DISH-easy method. RESULTS: The results from two pathologists using the DISH-easy method corresponded to the IHC results (P < 0.01) and the DISH count method results (P < 0.01). All cases determined to be negative using the DISH-easy method were also negative via the DISH count method with a corresponding rate of 100 % for both pathologist A (34/34) and B (32/32). Most of the results for the positive cases also corresponded; the correspondence rate of pathologist A was 100 % (8/8) and 89 % for B (8/9). The inter-observer concordance rate was 81 % (κ = 0.65). CONCLUSIONS: The DISH-easy method is simple and useful for HER2 testing regardless of proficiency of the evaluators.