Breast Surgical Oncology, The Cancer Institute Hospital of JFCR, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan.
Division of Cancer Genomic Medicine Development, Advanced Medical Development Center, The Cancer Institute Hospital of JFCR, Tokyo, Japan.
BMC Med. 2022 Apr 25;20(1):136. doi: 10.1186/s12916-022-02332-1.
Triple-negative breast cancer (TNBC) is a biologically diverse disease, with characteristics such as homologous recombination deficiency (HRD), gene mutation, and immune reactions. Japan Breast Cancer Research Group 22 is a multicenter trial examining TNBC's response to neoadjuvant chemotherapy (NAC) according to the HRD status. This translational research investigated the clinical significance of the immune microenvironment of TNBC in association with HRD, tumor BRCA1/2 (tBRCA1/2) mutation, and response to NAC.
Patients aged below 65 years with high HRD or germline BRCA1/2 (gBRCA1/2) mutation randomly received paclitaxel + carboplatin (group A1) or eribulin + carboplatin (A2), followed by anthracycline. Patients aged below 65 years with low HRD or those aged 65 years or older without gBRCA1/2 mutation randomly received eribulin + cyclophosphamide (B1) or eribulin + capecitabine (B2); nonresponders to the first four cycles of the therapy received anthracycline. A pathological complete response (pCR) was defined as the absence of residual cancer cells in the tissues. Pretreatment biopsy specimens were stained by multiplexed fluorescent immunohistochemistry using antibodies against CD3, CD4, CD8, Foxp3, CD204, and pan-cytokeratin. Immune cells with specific phenotypes were counted per mm in cancer cell nests (intratumor) and stromal regions. The immune cell densities were compared with clinicopathological and genetic factors including tumor response.
This study analyzed 66 samples. T1 tumors had a significantly higher density of intratumoral CD8 T cells than T2 or larger tumors. The tBRCA1/2 mutation or HRD status was not associated with the density of any immune cell. The density of intratumoral and stromal CD4 T cells was higher in patients showing pCR than in those without pCR. In a multivariate analysis, intratumoral and stromal CD4 T cell density significantly predicted pCR independent of age, chemotherapy dose, HRD status, and treatment groups (P = 0.009 and 0.0057, respectively). In a subgroup analysis, the predictive value of intratumoral and stromal CD4 T cell density persisted in the platinum-containing chemotherapy group (A1+A2) but not in the non-platinum-containing group (B1+B2).
Intratumoral and stromal CD4 T cell density was an independent predictor of pCR in patients with TNBC. A larger study is warranted to confirm the results.
UMIN000023162.
三阴性乳腺癌（TNBC）是一种具有同源重组缺陷（HRD）、基因突变和免疫反应等特征的生物学多样化疾病。日本乳腺癌研究组 22 是一项多中心试验，根据 HRD 状态检查 TNBC 对新辅助化疗（NAC）的反应。这项转化研究调查了与 HRD、肿瘤 BRCA1/2（tBRCA1/2）突变和 NAC 反应相关的 TNBC 免疫微环境的临床意义。
年龄在 65 岁以下、HRD 较高或种系 BRCA1/2（gBRCA1/2）突变的患者随机接受紫杉醇+卡铂（A1 组）或艾立布林+卡铂（A2），然后接受蒽环类药物。年龄在 65 岁以下 HRD 较低或 65 岁及以上无 gBRCA1/2 突变的患者随机接受艾立布林+环磷酰胺（B1 组）或艾立布林+卡培他滨（B2 组）；前四个周期治疗无反应的患者接受蒽环类药物。组织学完全缓解（pCR）定义为组织中无残留癌细胞。使用针对 CD3、CD4、CD8、Foxp3、CD204 和泛细胞角蛋白的多重荧光免疫组化对预处理活检标本进行染色。在肿瘤细胞巢（肿瘤内）和基质区域，每毫米计算具有特定表型的免疫细胞数。将免疫细胞密度与包括肿瘤反应在内的临床病理和遗传因素进行比较。
本研究分析了 66 个样本。T1 肿瘤的肿瘤内 CD8 T 细胞密度明显高于 T2 或更大的肿瘤。tBRCA1/2 突变或 HRD 状态与任何免疫细胞的密度均无关。与无 pCR 的患者相比，显示 pCR 的患者的肿瘤内和基质 CD4 T 细胞密度更高。在多变量分析中，肿瘤内和基质 CD4 T 细胞密度独立于年龄、化疗剂量、HRD 状态和治疗组（P=0.009 和 0.0057）预测 pCR。在亚组分析中，肿瘤内和基质 CD4 T 细胞密度在含铂化疗组（A1+A2）中预测 pCR 的价值持续存在，但在不含铂化疗组（B1+B2）中则不存在。
肿瘤内和基质 CD4 T 细胞密度是 TNBC 患者 pCR 的独立预测因子。需要更大的研究来证实这些结果。
UMIN000023162。
