Molecular Genetics of Lobular Breast Cancer in a South African cohort and effect of HIV infection. Breast cancer has become the most common malignancy among women in sub-Saharan Africa, and cause of cancer-related death. Changes in reproductive behaviours and westernized lifestyle factors are leading to increased breast cancer rates. Sub-Saharan Africa has nearly 70% of the world's cases of human immunodeficiency virus (HIV) and HIV incidence rates are rising faster among women than among men. There is evidence both from USA and Africa that HIV-infected cancer patients have poorer cancer-specific survival than HIV-uninfected patients, even after accounting for cancer stage and treatment. Data about prognosis in HIV-positive breast cancer patients are sparse.   Preliminary data from the South African Breast Cancer and HIV-Outcomes cohort study (SABCHO) reveals that breast cancer in HIV positive women occurs at younger age, has a higher mortality rate but has a similar subtype distribution to breast cancer in HIV cancer negative patients, with estrogen receptor positive (ER+) cancers being most common.  In this project we will use samples from the SABCHO study to investigate a subtype of breast cancer, known as lobular breast cancer that has distinct etiological, clinical and biological characteristics compared with the more common invasive ductal (IDC). There is some evidence that they are less chemo-sensitive than IDC and that the 10-year survival rate of women with ILC is lower than that of ER+ IDCs. ILC accounts for 10-15% of all invasive breast cancer in Western countries and is less frequent in lower and middle income countries presumably due to lifestyle factors and lack of hormone replacement therapy use. However, there is evidence from the USA that African Americans have more aggressive ILC and worse outcomes. It is also likely that with changes in reproductive behaviors and westernized lifestyle factors there will be an increase in lobular breast cancer in sub-Saharan Africa.  From the SABCHO study we have identified a series of 67 cases of ILC that occurred in black women of whom 13 (19%) are HIV positive with tissue blocks and blood samples available for analysis. The mean age at diagnosis of HIV positive patients was 45 years compared to 60 years for the HIV negative cases. The HIV positive cases were also more likely to present with stage 3-4 disease (77% vs 46%). Clinico-pathological features (age, nodal status, size, receptor status, grade and lymphocytic infiltrate) will be assessed in these samples and compared to a comparable UK cohort. We will also assess whether HIV infection has an effect on the composition of the lymphocytic infiltrate. Molecular differences will be assessed using targeted sequencing and copy number analysis.  As ILCs are more chemoresistant than IDCs the mainstay of treatment is Tamoxifen in premenopasual women. Tamoxifen is activated by liver enzymes to the therapeutic metabolite endoxifen, this activation can be affected by drugs such anti-retrovirals used in the treatment of HIV infection and by genetic variants of the liver enzymes, ~30% of African populations have such a genetic variant, CYP2D6*17. Patients for this study will be eligible if they have ILC or ER+ HER2-negative IDC and have been receiving tamoxifen treatment for at least 3 months. In this pilot phase 50 women who are on anti-retroviral therapy for HIV and 50 HIV-uninfected patients will have blood taken and analysed for tamoxifen and its metabolites and genotyped for genetic variants. This will allow us to study the effects of anti-retroviral therapy and the African-specific CYP2D6*17 polymorphism on tamoxifen metabolism.  We will also perform a small pilot to explore the utility of analysing levels of tumour mutations in plasma DNA from patients before and after therapy for metastatic ILC. This will be a small prospective study on ten patients (5 HIV+, 5 HIV-) collecting plasma before and after treatment. The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world.