Androgen receptor expression and associated clinico-pathologic features in primary breast cancer from Kenya

Introduction: Breast cancer is a heterogeneous group of diseases classified into various subtypes according to clinical, histological and molecular features as well as by the expression of prognostic and predictive biomarkers. New biomarkers are being studied which may be therapeutic targets in various breast cancer subtypes particularly triple-negative breast cancer. Recent studies show that androgen receptor (AR) expression can be used as a prognostic marker and there is evidence that anti-androgen therapy may be beneficial in oestrogen receptor negative breast cancer. Retrospective studies show that patients with breast cancers co-expressing androgen receptor and oestrogen receptor have a favourable prognosis and improved survival. On the other hand, oestrogen receptor-negative breast cancers which express the androgen receptor in the presence of the human epidermal growth factor-2 (HER2) over-expression are associated with an unfavourable prognosis. In addition there may be regional or even racial differences in the expression of the AR in breast cancer. The objective of this study was, therefore, to determine AR expression in breast cancers from Kenya and secondarily, to determine the association of AR expression with prognostic and predictive clinico-pathologic factors. Materials and Methods: The study was nested within a larger study based at AKUHN which is exploring the prevalence of triple-negative breast cancer in Kenya. Tissue blocks from 222 breast cancer specimens collected prospectively from September 2012 to March 2014 within the larger study were analysed for the presence of the androgen receptor. Tumour blocks were stained for AR on automated IHC platform. Nuclear staining of \u3e10% was used as the cut-off for a positive AR stain. Clinical pathological features, including the ER/PR/HER2 status, were captured from data recorded in the larger study. Results: Of the total 222 cases of breast cancer analyzed for the androgen receptor, 78.8% were found to be positive for AR expression (confidence interval 72.86 – 84.01). A third of the triple-negative breast cancer cases (33%) and 94% of HER2 subtype breast cancer cases were positive for androgen receptor expression. Androgen receptor expression was significantly associated with estrogen receptor expression (p = 0.000001) and Her2 subtype of breast cancer (p = 0.04). Androgen receptor expression followed the age distribution of the sample population and tended to be inversely related to tumour grade. However these findings were not statistically significant. No association was found between androgen receptor expression, tumour stage, lymph node status or specimen type. Conclusions: The androgen receptor is expressed in 79% of breast cancers in this study. This is similar to the levels of AR expression in published literature. The association between AR expression and ER expression is expected and has frequently been reported in literature. The strong association between AR expression and the HER2 subtypes of breast cancer is stronger than that reported in literature and should be explored. Further studies are needed to investigate patients with ER negative, AR positive breast cancers in view of the poorer prognosis in a subset of these patients and their potential to benefit from anti-androgen treatment

The untapped potential of digital pathology in prostate cancer diagnosis and medical education in sub-Saharan Africa

Introduction: Prostate cancer exerts a significant burden of disease in sub-Saharan Africa. Late clinical presentation with metastatic disease at diagnosis and the lack of structured national screening programs are unsolved issues. The delay in prostate cancer diagnosis is in part due to the severe shortage of African pathologists with inadequate or inaccessible diagnostic infrastructure playing a contributory role to this problem. Discussion: Digital pathology platforms could offer new solutions to the diagnostic and educational challenges facing pathologists practicing in Africa. For prostate cancer, they could provide several advantages including the assessment of biopsy cores, measurement of tumor volumes and second opinion consultation of difficult cases. They may also be an outstanding tool in developing Gleason tutorials for educational and standardization purposes. Conclusion: A transition to digital pathology in sub-Saharan Africa could yield incremental benefits to the quality of pathology diagnosis and highlight the growing capacity of digital pathology as a sub-speciality educational tool in the training of African pathologists both in prostate pathology and other pathology sub-specializations. Keywords: Prostate cancer, Digital pathology, Afric

Is breast cancer from Sub Saharan Africa truly receptor poor? Prevalence of ER/PR/HER2 in breast cancer from Kenya

Objectives: Studies on ER/PR/HER2 in breast cancer from Sub Saharan Africa (SSA) are fraught with inconsistencies in the prevalence of hormone receptor status. In Kenya, ER/PR/HER2 for breast cancers is not part of routine assessment and available in only three to four centers across the country. Variability in methodology and interpretation makes comparison between data difficult. Our aim was to accurately determine the prevalence of ER/PR/HER2 using standardized techniques and double reporting. Prognostic tumor parameters were also correlated with clinical features and receptor status. Materials and methods: Consecutive invasive breast cancers (IBC) accrued between September 2011 and December 2012 were analyzed at Aga Khan University Hospital, Nairobi (AKUHN). Tumor blocks were stained for ER/PR/HER2 on an automated platform. Double reporting of ER/PR/HER2 was done using the Allred system and the ASCO/CAP guidelines respectively. Results: A total of 301 cases of IBC were analyzed for pathology and ER/PR/HER2. The age range of patients was 19-94 years with a median of 47.5 years. Invasive ductal carcinoma (NOS) was the most common histologic type (84.2%). ER positivity was seen in 72.8%, PR in 64.8% and HER2 in 17.6% of all cases. Triple negative breast cancers (TNBC) constituted 20.2% of the cases. There was a significant association between receptor status and histologic grade (p \u3c 0.001) and statistically significant trend of increasing pathological stage of tumor (pT) associated with TNBC (p = 0.020). Conclusions: We present a definitive prospective analysis of ER/PR/HER2 from a single center and demonstrate that prevalence of receptor status from SSA is comparable with that in the West

Levels of innate immune factors in genital fluids : association of alpha defensins and LL-37 with genital infections and increased HIV acquisition

Background: Several mucosal innate immune proteins exhibit HIV inhibitory activity and their analogues are potential microbicide candidates. However, their clinical associations and in-vivo role in cervicovaginal host defense against HIV acquisition are poorly defined. Methods: Cervicovaginal secretions (CVSs) were collected from HIV uninfected Kenyan sex workers at enrolment into an HIV prevention trial. After trial completion, CVS from participants acquiring HIV (cases) and matched controls were assessed for levels of innate immune factors and HIV neutralizing capacity, by blinded investigators. Cross-sectional and prospective associations of innate immune factors were examined. Results: CVS contained high levels of defensins (human neutrophil peptide-1-3 and human beta defensin-2-3), LL-37 and secretory leukocyte protease inhibitor. Regulated upon activation normal T-cell expressed and secreted levels were lower, and IFN alpha was undetectable. CVS from 20% of participants neutralized a clade A primary HIV isolate, and 12% neutralized both clade A and C isolates. HIV neutralization was correlated with human neutrophil peptide-1-3 (alpha-defensins) and LL-37 levels. However, a.-defensin and LL-37 levels were increased in participants with bacterial sexually transmitted infections and were independently associated with increased HIV acquisition in multivariate analysis. Conclusions: Despite significant HIV inhibitory activity, cervicovaginal levels of alpha-defensins and LL-37 were associated with increased HIV acquisition, perhaps due to their association with bacterial sexually transmitted infections

HIV-neutralizing immunoglobulin A and HIV-specific proliferation are independently associated with reduced HIV acquisition in Kenyan sex workers

Objectives: HIV-neutralizing immunoglobulin A (IgA) and HIV-specific cellular immunity have been described in highly exposed, persistently seronegative (HEPS) individuals, but well controlled studies have not been performed. We performed a prospective, nested case-control study to examine the association of genital IgA and systemic cellular immune responses with subsequent HIV acquisition in high-risk Kenyan female sex workers (FSWs). Design and methods: A randomized trial of monthly antibiotic prophylaxis to prevent sexually transmitted disease/HIV infection was performed from 1998 to 2002 in HIV-uninfected Kenyan FSWs. After the completion of trial, FSWs who had acquired HIV (cases) were matched 1 : 4 with persistently uninfected controls based on study arm, duration of HIV-seronegative follow-up, and time of cohort enrolment. Blinded investigators assayed the ability at enrolment of genital IgA to neutralize primary HIV isolates as well as systemic HIV-specific cellular IFN gamma-modified enzyme-linked immunospot and proliferative responses. Results: The study cohort comprised 113 FSWs: 24 cases who acquired HIV and 89 matched controls. Genital HIV-neutralizing IgA was associated with reduced HIV acquisition (P= 0.003), as was HIV-specific proliferation (P= 0.002), and these associations were additive. HIV-specific IFN gamma production did not differ between case and control groups. In multivariable analysis, HIV-neutralizing IgA and HIV-specific proliferation each remained independently associated with lack of HIV acquisition. Genital herpes (HSV2) was associated with increased HIV risk and with reduced detection of HIV-neutralizing IgA. Conclusion: Genital HIV-neutralizing IgA and systemic HIV-specific proliferative responses, assayed by blinded investigators, were prospectively associated with HIV nonacquisition. The induction of these immune responses may be an important goal for HIV vaccines

Mucosal Neisseria gonorrhoeae coinfection during HIV acquisition is associated with enhanced systemic HIV-specific CD8 T-cell responses

Background: The host immune response against mucosally acquired pathogens maybe influenced by the mucosal immune milieu during acquisition. As Neisseria gonorrhoeae can impair dendritic cell and T-cell immune function, we hypothesized that coinfection during HIV acquisition would impair subsequent systemic T-cell responses. Methods: Monthly screening for sexually transmitted infections was performed ill high risk, HIV seronegative Kenyan female sex workers as part of an HIV prevention trial. Early HIV-specific CD8 T-cell responses and subsequent HIV viral load set point were assayed in participants acquiring HIV, and were correlated with the presence of prior genital infections during HIV acquisition. Results: Thirty-five participants acquired HIV during follow-up, and 16 out of 35 (46%.) had a classical sexually transmitted infection at the time of acquisition. N.gonorrhoeae coinfection was present during HIV acquisition in 6 out of 35 (17%), and was associated with an increased breadth and magnitude of systemic HIV-specific CD8 T-cell responses, using both interferon-gamma gamma and MIP-1 beta as an Output. No other genital infections were associated with differences in HIV-specific CD8 T-cell response, and neither N. gonorrhoeae nor other genital infections were associated with differences in HIV plasma viral load at set point. Conclusion: Unexpectedly, genital N. gonorrhoeae infection during heterosexual HIV acquisition was associated with substantially enhanced HIV-specific CD8 T-cell responses, although not with differences in HIV viral load set point. This may have implications for the development of mucosal HIV vaccines and adjuvants