The effects of bisphosphonate and radiation therapy in bone-metastatic lung adenocarcinoma: the impact of KRAS mutation

Abstract

Background: KRAS mutation is the most common genetic alteration in lung adenocarcinoma (LADC) in Western countries and is associated with worse outcome in bone-metastatic cases. Yet, to date, no effective treatment guidelines were developed for these patients. Accordingly, our aim was to investigate the impact of KRAS mutation on bisphosphonate (BTx) and radiation therapy (RTx) in bone-metastatic LADC patients.Methods: Clinicopathological variables of 134 consecutive LADC patients with bone metastases at diagnosis and known KRAS status were retrospectively analyzed. The effects of BTx, RTx and KRAS mutation on overall survival (OS) were investigated.Results: Of the total cohort, 93 patients were identified as KRAS wild-type (WT) (69.4%) and 41 (30.6%) as KRAS mutant patients. The presence of KRAS mutation was associated with significantly reduced median OS (5.1 vs. 10.2 months in KRAS WT patients; P=0.008). Irrespective of KRAS mutational status both BTx (P=0.007) and RTx (P=0.021) conferred a significant benefit for OS. Notably, however, when analyzing the patients with KRAS-mutant and KRAS WT tumors separately, the benefit from BTx and RTx on OS remained statistically significant only in KRAS WT patients (P=0.032 and P=0.031, respectively).Conclusions: KRAS mutation is a strong negative prognostic factor in bone-metastatic LADC patients.Both BTx and RTx can increase the OS with a pronounced benefit for patients with KRAS WT tumors.Altogether, KRAS mutational status should be considered during therapeutic decision making in bonemetastatic LADC patients.

Bone-Specific Metastasis Pattern of Advanced-Stage Lung Adenocarcinoma According to the Localization of the Primary Tumor

“…Of note, KRAS mutation was found to be a negative prognosticator in these patients. Therefore, KRAS mutational status should be considered when making decisions in bone metastatic LADC patient therapy ( 17 ). In addition, according to the “seed and soil” hypothesis, the histological subtype and the mutational status of the primary tumor might also have an impact on the specific metastasis patterns ( 38 , 39 ).…”

“…RTx is performed primarily for pain relief, control of a bone affected by metastases and prevention of pathologic fractures ( 15 , 16 ). Of note, oncogenic driver mutations should be taken into consideration during the administration of BTx and RTx since the beneficial effects of both therapeutic modalities might be less pronounced in patients with KRAS mutant tumors ( 17 ).…”

KRASG12C mutant lung adenocarcinoma: unique biology, novel therapies and new challenges

“…Another retrospective analysis tested the efficacy of bevacizumab in combination with chemotherapy and demonstrated that it is more efficient in KRAS wild-type tumors which was due to the resistance of the G12D mutant form [ 15 ]. Analysis of the treatment outcome of bone metastatic lung carcinoma patients indicated that the KRAS mutant tumors seems to be resistant to radiation therapy and to bisphosphonates [ 16 ] as it was predicted by the preclinical models [ 17 ]. A recent analysis of the G12D mutant lung cancers demonstrated that the density of CD8 + T cells, the TMB and the tumor cell expression level of PDL1 are lower as compared to other KRAS mutants including G12C [ 18 ].…”

PD‐1+CXCR5‐CD4+ T cells are correlated with the severity of lung adenocarcinoma malignant processes

“…Lung cancer is the leading cause of cancer‐related incidence and mortality, with non‐small‐cell lung cancer (NSCLC) as the most prevalent form with a poor 5 years survival of ~15% 1‐3 . Lung adenocarcinoma (LADC), characterized by high malignancy, short overall survival and loss of functional independence, is constituting the majority of newly diagnosed NSCLC cases and continuously rising in incidence 4‐6 . Unfortunately, the majority of patients already have advanced‐stage disease at diagnosis with different types of distant organ metastases 5 .…”

“…Lung adenocarcinoma (LADC), characterized by high malignancy, short overall survival and loss of functional independence, is constituting the majority of newly diagnosed NSCLC cases and continuously rising in incidence 4‐6 . Unfortunately, the majority of patients already have advanced‐stage disease at diagnosis with different types of distant organ metastases 5 . In addition to surgery, LADC therapy includes radiation therapy, chemotherapy, molecule‐targeted therapy and cellular immunotherapy, which has been gradually maturing in recent years 1 .…”