Molecular Genetics of Lobular Breast Cancer in a South African cohort and effect of HIV infection.

乳腺癌已成为撒哈拉以南非洲妇女中最常见的恶性肿瘤，也是癌症相关死亡的原因。生殖行为的改变和西方化的生活方式因素导致乳腺癌发病率上升。撒哈拉以南非洲地区的人类免疫缺陷病毒（艾滋病毒）病例占世界病例的近70%，而且艾滋病毒在女性中的发病率上升速度快于男性。来自美国和非洲的证据表明，感染艾滋病毒的癌症患者的癌症特异性生存率低于未感染艾滋病毒的患者，即使在考虑了癌症分期和治疗后也是如此。关于hiv阳性乳腺癌患者预后的数据很少。来自南非乳腺癌和艾滋病毒结局队列研究（SABCHO）的初步数据显示，艾滋病毒阳性妇女的乳腺癌发生年龄较年轻，死亡率较高，但与艾滋病毒癌症阴性患者的乳腺癌具有相似的亚型分布，雌激素受体阳性（ER+）癌症最常见。在这个项目中，我们将使用来自SABCHO研究的样本来研究一种被称为小叶型乳腺癌的亚型，与更常见的浸润性导管（IDC）相比，它具有独特的病因学、临床和生物学特征。有证据表明，它们的化疗敏感性低于IDC，并且ILC妇女的10年生存率低于ER+ IDC妇女。在西方国家，ILC占所有浸润性乳腺癌的10-15%，在中低收入国家发病率较低，可能是由于生活方式因素和缺乏激素替代疗法的使用。然而，有来自美国的证据表明，非裔美国人的ILC更具侵略性，结果更差。随着生殖行为的改变和西方化的生活方式因素，撒哈拉以南非洲地区小叶性乳腺癌的发病率也可能会增加。从SABCHO研究中，我们确定了一系列67例黑人妇女的ILC，其中13例（19%）是HIV阳性，组织块和血液样本可用于分析。HIV阳性患者的平均诊断年龄为45岁，而HIV阴性患者的平均诊断年龄为60岁。艾滋病毒阳性病例也更有可能出现3-4期疾病（77%对46%）。将评估这些样本的临床病理特征（年龄、淋巴结状态、大小、受体状态、分级和淋巴细胞浸润），并与英国同类队列进行比较。我们还将评估HIV感染是否对淋巴细胞浸润的组成有影响。分子差异将通过靶向测序和拷贝数分析进行评估。由于ILCs比IDCs更耐化疗，绝经前妇女的主要治疗是他莫昔芬。他莫昔芬由肝酶激活产生治疗代谢产物内毒素，这种激活可受到治疗HIV感染的抗逆转录病毒药物和肝酶的遗传变异的影响，约30%的非洲人口有这种遗传变异CYP2D6*17。如果患者患有ILC或ER+ her2阴性IDC，并且接受他莫昔芬治疗至少3个月，则该研究的患者将符合条件。在这一试点阶段，将抽取50名接受艾滋病毒抗逆转录病毒治疗的妇女和50名未感染艾滋病毒的患者的血液，分析其他莫昔芬及其代谢物，并对遗传变异进行基因分型。这将使我们能够研究抗逆转录病毒治疗和非洲特异性CYP2D6*17多态性对他莫昔芬代谢的影响。我们还将进行一个小型试点，以探索分析转移性ILC治疗前后患者血浆DNA中肿瘤突变水平的效用。这将是一项小型前瞻性研究，对10例患者（5例HIV+， 5例HIV-）在治疗前后收集血浆。

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.