Targeting KRAS in NSCLC: Old Failures and New Options for “Non-G12c” Patients

Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene mutations are among the most common driver alterations in non-small cell lung cancer (NSCLC). Despite their high frequency, valid treatment options are still lacking, mainly due to an intrinsic complexity of both the protein structure and the downstream pathway. The increasing knowledge about different mutation subtypes and co-mutations has paved the way to several promising therapeutic strategies. Despite the best results so far having been obtained in patients harbouring KRAS exon 2 p.G12C mutation, even the treatment landscape of non-p.G12C KRAS mutation positive patients is predicted to change soon. This review provides a comprehensive and critical overview of ongoing studies into NSCLC patients with KRAS mutations other than p.G12C and discusses future scenarios that will hopefully change the story of this disease.

MỐI LIÊN QUAN GIỮA TÌNH TRẠNG ĐỘT BIẾN GEN KRAS, NRAS, BRAF VÀ MỘT SỐ ĐẶC ĐIỂM BỆNH HỌC UNG THƯ BIỂU MÔ ĐẠI TRỰC TRÀNG GIAI ĐOẠN DI CĂN

Mục tiêu: (1) Xác định tỷ lệ đột biến gen KRAS, NRAS và BRAF ở bệnh nhân ung thư đại trực tràng di căn; (2) Đối chiếu tình trạng đột biến gen với một số đặc điểm bệnh học của bệnh nhân ung thư đại trực tràng di căn. Đối tượng và phương pháp nghiên cứu: Mô tả cắt ngang 76 trường hợp ung thư biểu mô đại trực tràng giai đoạn di căn được chẩn đoán và điều trị tại Bệnh viện TWQĐ 108. Giải trình tự chuỗi DNA gen KRAS (exon 2), NRAS (exon 2, 3, 4) và BRAF (exon 15) để xác định tình trạng đột biến và mối liên quan với một số đặc điểm bệnh học. Kết quả: Trong 76 trường hợp khảo sát gen KRAS, NRAS và BRAF chúng tôi ghi nhận tỷ lệ đột biến gen lần lượt là 44,7%; 3,9% và 9,2%. Đột biến gen KRAS thường gặp ở các bệnh nhân có nồng độ CEA huyết thanh tại thời điểm chẩn đoán > 5ng/ml với p = 0,022. Đột biến gen BRAF thường gặp ở các bệnh nhân có nồng độ CEA huyết thanh tại thời điểm chẩn đoán > 20ng/ml với p = 0,007. Các đặc điểm bệnh học khác như nhóm tuổi, giới, thể trạng, vị trí khối u nguyên phát, độ mô học và số lượng tạng di cănliên quan không có ý nghĩa với tình trạng đột biến gen KRAS và BRAF. Không tìm thấy mối liên quan có ý nghĩa giữa tình trạng đột biến gen NRAS và các đặc điểm bệnh học. Kết luận: Tỷ lệ đột biến gen KRAS ở bệnh nhân ung thư biểu mô tuyến đại trực tràng giai đoạn di căn tại bệnh viện TWQĐ 108 là 44,7%. Đột biến gen KRAS liên quan có ý nghĩa với nồng độ CEA huyết thanh tại thời điểm chẩn đoán (> 5ng/ml). Tỷ lệ đột biến gen NRAS là 3,9%. Tỷ lệ đột biến gen BRAF là 9,2%. Đột biến gen BRAF liên quan có ý nghĩa với nồng độ CEA huyết thanh tại thời điểm chẩn đoán (> 20ng/ml).

Case Report: Outcome of Osimertinib Treatment in Lung Adenocarcinoma Patients With Acquired KRAS Mutations

BackgroundOsimertinib belongs to the third-generation epidermal growth factor receptor tyrosine kinase inhibitor that has shown positive effects in treating lung adenocarcinoma cancer. However, the subsequent resistance to Osimertinib has become a clinical challenge.Case PresentationWe present two lung adenocarcinoma cases that developed a resistance to Osimertinib. Among them, one patient attained both KRAS exon 2 and exon 3 mutations and was given paclitaxel (albumin-bound) plus carboplatin. The other patient exhibited a KRAS exon 3 mutation, so the paclitaxel (albumin-bound) plus nivolumab was administered. Eventually, the second patient manifested a better clinical outcome than the first.ConclusionThese results provide supporting evidence that KRAS exon 3 (R68S) mutations may be associated with Osimertinib resistance in lung adenocarcinoma patients. This further reveals the relationship between subtypes of acquired KRAS mutations and the effect of therapeutic approaches. Moreover, the combination of chemotherapy and immune checkpoint inhibitors may generate a satisfying disease control.

Mutation status and prognostic value of KRAS and NRAS mutations in Moroccan colon cancer patients: A first report

This study aimed to estimate the incidence of KRAS, NRAS, and BRAF mutations in the Moroccan population, and investigate the associations of KRAS and NRAS gene mutations with clinicopathological characteristics and their prognosis value. To achieve these objectives, we reviewed medical and pathology reports for 210 patients. RAS testing was investigated by Sanger sequencing and Pyrosequencing technology. BRAF (exon 15) status was analyzed by the Sanger method. The expression of MMR proteins was evaluated by Immunohistochemistry. KRAS and NRAS mutations were found in 36.7% and 2.9% of 210 patients, respectively. KRAS exon 2 mutations were identified in 76.5% of the cases. RAS-mutated colon cancers were significantly associated with female gender, presence of vascular invasion, classical adenocarcinoma, moderately differentiated tumors, advanced TNM stage III-IV, left colon site, higher incidence of distant metastases at the time of diagnostic, microsatellite stable phenotype, lower number of total lymph nodes, and higher means of positive lymph nodes and lymph node ratio. KRAS exon 2-mutated colon cancers, compared with KRAS wild-type colon cancers were associated with the same clinicopathological features of RAS-mutated colon cancers. NRAS-mutated patients were associated with lower total lymph node rate and the presence of positive lymph node. Rare RAS-mutated tumors, compared with wild-type tumors were more frequently moderately differentiated and associated with lower lymph node rate. We found that KRAS codon 13-mutated, tumors compared to codon 12-mutated tumors were significantly correlated with a higher death cases number, a lower rate of positive lymph, lower follow-up time, and poor overall survival. Our findings show that KRAS and NRAS mutations have distinct clinicopathological features. KRAS codon 13-mutated status was the worst predictor of prognosis at all stages in our population.

Concomitant Rare KRAS and BRAF Mutations in Lung Adenocarcinoma: A Case Report

In July 2020, an active smoker, 63-year old man was admitted to the oncology unit of A.O.R.N. Sant’Anna e San Sebastiano (Caserta, Italy). Chest radiology highlighted right pleural effusion. Total-body CT scanning revealed a solid lesion with lobulated contours in the apical segment of the upper right lobe. The patient’s oncologist requested a molecular assessment of EGFR, ALK, ROS1, BRAF, and KRAS, as well as an evaluation of PD-L1 expression level. To this end, we carried out NGS analysis, on DNA extracted from cytospins, by adopting a custom-designed NGS panel (SiRe®). Overall, no actionable mutations in the tested genes were identified. Conversely, concomitant BRAF exon 11 p.G469A and a KRAS exon 4 p.A146T mutations were detected. Owing to the limited data on the presence of KRAS exon 4 p.A146T point mutation in lung adenocarcinoma patients, a further molecular confirmatory analysis was carried out with a dedicated KRAS cartridge on a fully automated real time polymerase chain reaction. When DNA was extracted from the TTF-1 positive tumor cell slide, the same KRAS alteration was observed. Unfortunately, the patient died in August 2020 before having the chance to start any type of treatment.

Dramatic Response of Pulmonary Sarcomatoid Carcinoma to Nivolumab Combined with Anlotinib: A Case Report

Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small-cell lung cancer, which is resistant to the conventional chemotherapy and radiotherapy with a poor prognosis. Limited case reports have showed good response to the immunotherapy in PSC patients with high PD-L1 expression generally. Herein, we report a case of rapid recurrence of PSC during postoperative adjuvant chemotherapy in a 62-year-old male ex-smoker. The patient had high PD-L1 expression (tumor proportion score: 90%) and KRAS exon 2 mutation. Nivolumab combined with anlotinib was administered synchronously. Clinical symptoms gradually relieved and response evaluation on imaging revealed a partial response after 8 weeks. This case suggests immunotherapy combined with antiangiogenic agent anlotinib may be a potential promising strategy to treat PSC patients.