ABSTRACT
This study aimed to conduct a comprehensive analysis of actionable gene rearrangements in tumors with microsatellite instability (MSI). The detection of translocations involved tests for 5'/3'-end expression imbalance, variant-specific PCR and RNA-based next generation sequencing (NGS). Gene fusions were detected in 58/471 (12.3%) colorectal carcinomas (CRCs), 4/69 (5.8%) gastric cancers (GCs) and 3/65 (4.6%) endometrial cancers (ECs) (ALK: 8; RET: 12; NTRK1: 24; NTRK2: 2; NTRK3: 19), while none of these alterations were observed in five cervical carcinomas (CCs), four pancreatic cancers (PanCs), three cholangiocarcinomas (ChCs) and two ovarian cancers (OCs). The highest frequency of gene rearrangements was seen in KRAS/NRAS/BRAF wild-type colorectal carcinomas (53/204 (26%)). Surprisingly, as many as 5/267 (1.9%) KRAS/NRAS/BRAF-mutated CRCs also carried tyrosine kinase fusions. Droplet digital PCR (ddPCR) analysis of the fraction of KRAS/NRAS/BRAF mutated gene copies in kinase-rearranged tumors indicated that there was simultaneous co-occurrence of two activating events in cancer cells, but not genetic mosaicism. CRC patients aged above 50 years had a strikingly higher frequency of translocations as compared to younger subjects (56/365 (15.3%) vs. 2/106 (1.9%), p = 0.002), and this difference was particularly pronounced for tumors with normal KRAS/NRAS/BRAF status (52/150 (34.7%) vs. 1/54 (1.9%), p = 0.001). There were no instances of MSI in 56 non-colorectal tumors carrying ALK, ROS1, RET or NTRK1 rearrangements. An analysis of tyrosine kinase gene translocations is particularly feasible in KRAS/NRAS/BRAF wild-type microsatellite-unstable CRCs, although other categories of tumors with MSI also demonstrate moderate occurrence of these events.
Subject(s)
Bile Duct Neoplasms , Cholangiocarcinoma , Colorectal Neoplasms , Female , Humans , Aged , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins B-raf , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins/genetics , Receptor Protein-Tyrosine Kinases , Microsatellite Repeats , Microsatellite Instability , Translocation, Genetic , Gene Fusion , Bile Ducts, Intrahepatic , Colorectal Neoplasms/genetics , Proto-Oncogene Proteins c-ret/geneticsABSTRACT
Early clinical trials aimed to halt cancer progression by inhibiting the growth of new blood vessels in tumors through single-agent targeted therapy with bevacizumab. These trials largely proved unsuccessful. However, bevacizumab turned out to be efficient when administered in combination with other anticancer drugs. The efficacy of this approach is explained by the ability of bevacizumab to eliminate immature blood vessels thus normalizing intratumoral blood flow and improving the delivery of cytotoxic or targeted agents. This report describes four cases of heavily pretreated patients with metastatic HER2-positive breast cancer, who had no meaningful treatment options left, and who received single-agent bevacizumab as an empirical last-resort therapy. Three of these patients had severe complaints, and they demonstrated striking symptomatic relief within the first day of this treatment. In addition to the observed "Lazarus response", which was likely attributed to the bevacizumab-driven resolution of edema, some evidence of a direct antitumor effect was observed. These data may call for the reconsideration of bevacizumab monotherapy in patients with HER2-associated breast cancer, and perhaps in some other categories of cancer patients.