Division of Surgical Oncology, Department of Surgery, Oregon Health & Science University, Portland.
Division of General Surgery, Department of Surgery, Oregon Health & Science University, Portland.
Surgery. 2019 May;165(5):1008-1013. doi: 10.1016/j.surg.2019.01.001. Epub 2019 Feb 15.
Approximately 70% of breast cancer patients have residual disease after neoadjuvant chemotherapy. This study was designed to determine whether breast cancer cells with stemlike properties are present in residual disease after neoadjuvant chemotherapy and whether they exhibit oncogenic mutations. The presence of breast cancer cells with stemlike properties with specific mutations may help explain the poor prognosis associated with residual disease.
A total of 68 breast cancer specimens were collected at the time of mastectomy or lumpectomy. A total of 44 were chemotherapy naïve and 24 were collected as residual disease after neoadjuvant chemotherapy. Tumor cells were collected by fluorescence-activated cell sorting, with breast cancer cells with stemlike properties specifically identified using breast stem cell associated antibodies. Whole tumor specimens and fluorescence-activated cell sorting breast cancer cells with stemlike properties were analyzed for genetic mutations, including PIK3CA.
Breast cancer cells with stemlike properties, demonstrating EpCAM-positive, CD44-positive, CD49f, CD24 expression were present in chemotherapy-naïve tumors and residual disease. In both chemotherapy-naïve and residual disease specimens the highest frequency of PIK3CA mutations were detected in CD49f-CD24+ BCSCs (39% and 33%, respectively). PIK3CA mutations were detected in all stages of breast cancer (35%), in both chemotherapy naïve (39%) and residual disease (29%) and in both estrogen receptor positive (41%) and negative tumors (14%) (P = ns). Various PIK3CA mutations were identified in chemotherapy-naïve specimens versus residual disease specimens in both patient-paired and unpaired breast cancers.
Breast cancer cells with stemlike properties with mutations in PIK3CA were present in chemotherapy-naïve breast cancers and residual disease after neoadjuvant chemotherapy. These results demonstrate that neoadjuvant chemotherapy does not completely eradicate PIK3CA-defective breast cancer cells with stemlike properties. Although these findings may help explain the poor clinical outcomes in patients with residual disease, they also identify breast cancer cells with stemlike-property targets for therapies.
大约 70%的乳腺癌患者在新辅助化疗后仍有残留疾病。本研究旨在确定新辅助化疗后残留疾病中是否存在具有干细胞样特性的乳腺癌细胞，以及它们是否存在致癌突变。具有特定突变的具有干细胞样特性的乳腺癌细胞的存在可能有助于解释与残留疾病相关的不良预后。
共收集了 68 例乳腺癌标本，分别在乳房切除术或肿块切除术时采集。其中 44 例为化疗初治患者，24 例为新辅助化疗后残留疾病患者。通过荧光激活细胞分选收集肿瘤细胞，使用乳腺癌干细胞相关抗体特异性鉴定具有干细胞样特性的乳腺癌细胞。对全肿瘤标本和荧光激活细胞分选的具有干细胞样特性的乳腺癌细胞进行基因突变分析，包括 PIK3CA。
在化疗初治肿瘤和残留疾病中均存在具有干细胞样特性的乳腺癌细胞，表现为 EpCAM 阳性、CD44 阳性、CD49f、CD24 表达。在化疗初治和残留疾病标本中，CD49f-CD24+BCSCs 中 PIK3CA 突变频率最高（分别为 39%和 33%）。PIK3CA 突变在所有乳腺癌分期（35%）、化疗初治（39%）和残留疾病（29%）以及雌激素受体阳性（41%）和阴性肿瘤（14%）中均有发现（P=ns）。在配对和非配对乳腺癌患者的化疗初治标本与残留疾病标本中均发现了不同的 PIK3CA 突变。
在化疗初治乳腺癌和新辅助化疗后残留疾病中均存在具有 PIK3CA 突变的具有干细胞样特性的乳腺癌细胞。这些结果表明，新辅助化疗并不能完全消除具有干细胞样特性的 PIK3CA 缺陷型乳腺癌细胞。尽管这些发现可能有助于解释残留疾病患者的不良临床结局，但它们也为针对具有干细胞样特性的乳腺癌细胞的治疗提供了靶点。
