Germinal centres within tumour positive sentinel lymph nodes are positively associated with tumour infiltrating lymphocytes and tertiary lymphoid structures in breast cancer.

BACKGROUND: Stromal tumour infiltrating lymphocytes (sTILs) and presence of tertiary lymphoid structures have been proposed as indicators of tumour-related immune response in breast cancer. An increased number of germinal centres (GCs) in lymph nodes is considered a sign of humoral immune reactivity. AIMS: It is unclear whether a relationship exists between number and size of GCs within tumour positive sentinel lymph nodes (SLNpos), sTILs and tertiary lymphoid structures within matched primary breast cancer and breast cancer subtype. METHODS: Axillary SLNpos from 175 patients with breast cancer were manually contoured in digitized haematoxylin and eosin stained sections. Total SLN area, GC number and GC area were measured in SLNpos with the largest metastatic area. To correct for SLN size, GC number and GC area were divided by SLN area. sTILs and presence of tertiary lymphoid structures were assessed in the primary breast cancer. RESULTS: A higher GC number and larger GC area were found in patients with high sTILs (≥2%) (both P < 0.001) and in patients with presence of tertiary lymphoid structures (PGC number = 0.034 and PGC area = 0.016). Triple negative and HER2-positive (N = 45) breast cancer subtypes had a higher GC number and higher sTILs compared to hormone receptor positive, HER2-negative breast cancer (N = 130) (PGC number < 0.001 and PsTILs= 0.001). CONCLUSION: This study suggests GCs measured within SLNpos might be useful indicators of the humoral anti-tumour immune response in breast cancer. Future studies are needed investigating underlying biological mechanisms and prognostic value of GCs in SLNs.

The prognostic value of the histological shape of tumor negative sentinel nodes in breast cancer.

Introduction: Sentinel lymph node (SLN) metastasis is an important predictor of prognosis in breast cancer (BC) patients, guiding treatment decisions. However, patients with the same BC subtype and tumor negative SLN (SLNneg) can have different survival outcomes. We hypothesized that the host anti-tumor immune reaction in SLNneg is important and results in morphometrically measurable changes in SLN size or shape which are related to patient prognosis. Methods: Surface area, circumference, long axis and short axis were histologically measured in 694 SLNneg from 356 cases of invasive BC and 67 ductal carcinoma in situ cases. The area occupied by fat was categorized as less or more than 50%. The long to short axis (L/S) ratio was calculated. The relationship between SLNneg morphometries and clinicopathological variables like tumor-infiltrating lymphocytes (TILs) within the primary tumor, as well as prognosis at 10 years follow up were analyzed. Results: The mean SLNneg surface area was 78.7mm2, circumference 40.3mm, long axis 13.1mm, short axis 8.2mm and L/S ratio 1.7. Larger surface area, long axis and short axis, including age >55 years were associated with higher body mass index (BMI) and SLN fat over 50% (p<0.003). In invasive BC, a high SLNneg L/S ratio (≥1.9) was related to poorer disease-free (HR=1.805, 95%CI 1.182-2.755, p=0.006) and overall (HR=2.389, 95%CI 1.481-3.851, p<0.001) survival. A low SLNneg L/S ratio (<1.9) was associated with high TILs in the primary BC (≥10%) (p=0.005). However a high TIL count was not of prognostic relevance. Conclusions: This is the first study to suggest that morphometric characteristics of axillary SLNneg, like L/S ratio, could be used to predict prognosis in patients with SLNneg invasive BC of all subtypes. The association between low L/S ratio and high TILs suggest that SLN shape is related to immunological functioning of the SLN and could be used in addition to TIL evaluation. Regarding the dubious role of TILs in hormone receptor positive breast cancer, SLNneg morphometry to gain information about host immune status could especially be of benefit in this subtype. Further studies are warranted to better understand the underlying biological mechanisms.

How the Gut Microbiome Links to Menopause and Obesity, with Possible Implications for Endometrial Cancer Development.

Background: Interest is growing in the dynamic role of gut microbiome disturbances in human health and disease. No direct evidence is yet available to link gut microbiome dysbiosis to endometrial cancer. This review aims to understand any association between microbiome dysbiosis and important risk factors of endometrial cancer, high estrogen levels, postmenopause and obesity. Methods: A systematic search was performed with PubMed as primary database. Three separate searches were performed to identify all relevant studies. Results: Fifteen studies were identified as highly relevant and included in the review. Eight articles focused on the relationship with obesity and eight studies focused on the menopausal change or estrogen levels. Due to the heterogeneity in patient populations and outcome measures, no meta-analysis could be performed. Both the menopausal change and obesity were noted to enhance dysbiosis by reducing microbiome diversity and increasing the Firmicutes to Bacteroidetes ratio. Both also incurred estrobolome changes, leading to increased systemic estrogen levels, especially after menopause. Furthermore, microbiome dysbiosis was reported to be related to systemic inflammation through toll-like receptor signaling deficiencies and overexpression of pro-inflammatory cytokines. Conclusions: This review highlights that the female gut microbiome is intrinsically linked to estrogen levels, menopausal state and systemic inflammation, which indicates gut microbiome dysbiosis as a potential hallmark for risk stratification for endometrial cancer. Studies are needed to further define the role the gut microbiome plays in women at risk for endometrial cancer.

Exploring the Potential of Breast Microbiota as Biomarker for Breast Cancer and Therapeutic Response.

Breast cancer tissue contains its own unique microbiota. Emerging preclinical data indicates that breast microbiota dysbiosis contributes to breast cancer initiation and progression. Furthermore, the breast microbiota may be a promising biomarker for treatment selection and prognosis. Differences in breast microbiota composition have been found between breast cancer subtypes and disease severities that may contribute to immunosuppression, enabling tumor cells to evade immune destruction. Interactions between breast microbiota, gut microbiota, and immune system are proposed, all forming potential targets to increase therapeutic efficacy. In addition, because the gut microbiota affects the host immune system and systemic availability of estrogen and bile acids known to influence tumor biology, gut microbiota modulation could be used to manipulate breast microbiota composition. Identifying breast and gut microbial compositions that respond positively to certain anticancer therapeutics could significantly reduce cancer burden. Additional research is needed to unravel the complexity of breast microbiota functioning and its interactions with the gut and the immune system. In this review, developments in the understanding of breast microbiota and its interaction with the immune system and the gut microbiota are discussed. Furthermore, the biomarker potential of breast microbiota is evaluated in conjunction with possible strategies to target microbiota in order to improve breast cancer treatment.