Aggressive breast cancer in western Kenya has early onset, high proliferation, and immune cell infiltration

Background Breast cancer incidence and mortality vary significantly among different nations and racial groups. African nations have the highest breast cancer mortality rates in the world, even though the incidence rates are below those of many nations. Differences in disease progression suggest that aggressive breast tumors may harbor a unique molecular signature to promote disease progression. However, few studies have investigated the pathology and clinical markers expressed in breast tissue from regional African patient populations. Methods We collected 68 malignant and 89 non-cancerous samples from Kenyan breast tissue. To characterize the tumors from these patients, we constructed tissue microarrays (TMAs) from these tissues. Sections from these TMAs were stained and analyzed using immunohistochemistry to detect clinical breast cancer markers, including estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor 2 receptor (HER2) status, Ki67, and immune cell markers. Results Thirty-three percent of the tumors were triple negative (ER-, PR-, HER2-), 59 % were ER+, and almost all tumors analyzed were HER2-. Seven percent of the breast cancer patients were male, and 30 % were <40 years old at diagnosis. Cancer tissue had increased immune cell infiltration with recruitment of CD163+ (M2 macrophage), CD25+ (regulatory T lymphocyte), and CD4+ (T helper) cells compared to non-cancer tissue. Conclusions We identified clinical biomarkers that may assist in identifying therapy strategies for breast cancer patients in western Kenya. Estrogen receptor status in particular should lead initial treatment strategies in these breast cancer patients. Increased CD25 expression suggests a need for additional treatment strategies designed to overcome immune suppression by CD25+ cells in order to promote the antitumor activity of CD8+ cytotoxic T cells

Tumor infiltrating leukocyte density is independent of tumor grade and molecular subtype in aggressive breast cancer of Western Kenya

Abstract Background Tumors commonly are infiltrated by leukocytes, or tumor infiltrating leukocytes (TILs). It remains unclear, however, if the density and type of individual TILs has a direct or simply correlative role in promoting poor prognosis in breast cancer patients. Breast cancer in Kenyan women is aggressive with presentation at a young age, with advanced grade (grade III), large tumor size (>2.0 cm), and poor prognosis. We previously observed that the tumors were predominantly estrogen receptor positive (ER+) but also included both a high percentage of triple negative tumors and also increased immune cell infiltration within the tumors. We used breast tumor tissues from each patient to make tissue microarrays that were then stained for leukocyte and myeloid markers including CD4, CD8, CD20, CD25, CD68, and CD163 using immunohistochemical techniques. The immune cell infiltration into the cancer tissue included increased numbers of macrophages (CD68+), helper T cells (CD4+), and CD25+ lymphocytes compared to benign tissue. Results This study characterized the grade, molecular subtypes, and proliferation index of these tumors and determined if TIL density was enriched across any of these factors. We analyzed 49 malignant patient tissue samples for this study. The patient population had a mean age of 51.9 years. The tumors analyzed were heterogeneous by grade: grade I (6%), grade II (47%), and grade III (39%). Most patients presented with large tumors (>2.0 cm) (69%). We classified the tumors into molecular subtypes based on clinical marker expression. Based on this analysis, the molecular subtype distribution was heterogeneous with luminal B (41%), basal/triple negative (TN) (37%), luminal A (14%) and HER2 (8%) breast cancer subtypes. While the basal/TN subtype had a much higher proliferative index (Ki-67+) than did the other molecular subtypes, we did not see a significant correlation between TIL density and either subtype or tumor grade. Therefore, TIL density is independent of molecular subtype and grade. Conclusion This study identified a Kenyan patient cohort that develops large, high-grade tumors primarily of the luminal B and basal molecular subtypes. After analyzing the TILs within these tumors, we found that immune cell infiltration of these tumors correlated with increased proliferation but not grade or molecular subtype. Future research is required to determine if the aberrant recruitment of TILs to tumors contributes to cancer progression and response to cancer treatments

Pathology-supported genetic testing for the application of breast cancer pharmacodiagnostics: family counselling, lifestyle adjustments and change of medication

Pathology-supported genetic testing (PSGT) enables transitioning of risk stratification from the study population to the individual. We provide an overview of the translational research performed in postmenopausal breast cancer patients at increased risk of osteoporosis due to aromatase inhibitor therapy, as the indication for referral. Both tumor histopathology and blood biochemistry levels were assessed to identify actionable disease pathways using whole exome sequencing (WES). The causes and consequences of inadequate vitamin D levels as a modifiable risk factor for bone loss were highlighted in 116 patients with hormone receptor-positive breast cancer. Comparison of lifestyle factors and WES data between cases with vitamin D levels at extreme upper and lower ranges identified obesity as a major discriminating factor, with the lowest levels recorded during winter. Functional polymorphisms in the vitamin D receptor gene contributed independently to therapy-related osteoporosis risk. In a patient with invasive lobular carcinoma, genetic counseling facilitated investigation of the potential modifying effect of a rare CDH1 variant co-occurring with BRCA1 c.66dup (p.Glu23ArgfsTer18). Validation of PSGT as a three-pronged pharmacodiagnostics tool for generation of adaptive reports and data reinterpretation during follow-up represents a new paradigm in personalized medicine, exposing significant limitations to overcome.</p