In both cases, the patients were successfully treated with discontinuation of the ICI agent and systemic corticosteroids [77,78]. emtansine to directly deliver chemotherapy to HER-2 positive cancer cells for antitumor effects [42]. Targeted therapies against HER-2 such as trastuzumab/trastuzumab emtansine have contributed to improved outcomes in HER-2 positive breast cancers and now are being evaluated for activity against other HER-2 positive cancers [43]. While trastuzumab continues to be widely used in the treatment of HER-2 positive tumors, it also can cause hepatotoxicity via direct damage to hepatocytes and subsequent upregulation of TNF-alpha signaling that further contributes to hepatocyte damage [44]. Case reports of hepatotoxicity secondary to trastuzumab continue to be published, including a patient who experienced elevated LFTs six months after starting trastuzumab, a patient who experienced recurrent LFT elevations with trastuzumab rechallenge, and two patients who experienced long term hepatic veno-occlusive disease years after treatment [45-47]. In the first two cases in which the patients experienced increased LFTs, discontinuation of trastuzumab administration was sufficient for the LFT levels to return to normal [45,46]. Treatment of the patients experiencing hepatic veno-occlusive disease involved management and treatment of sequela of portal hypertension including esophageal varices and hepatic encephalopathy [47]. Data from clinical trials has allowed for estimation of trastuzumab/trastuzumab emtansine hepatotoxicity rates. A prospective, phase II study of Japanese breast cancer patients receiving trastuzumab emtansine found that 60.3% of patients experienced any grade hepatotoxicity with AST/ALT elevations as the most commonly occurring hepatotoxic event. However, the hepatotoxicity for nearly all the patients was transient with only one patient requiring a dose decrease due to liver damage [48]. Additional data from a meta-analysis of seven trials of breast cancer patients found that those receiving trastuzumab emtansine had a relative risk of 3.24 for experiencing all-grade AST/ALT elevation vs control treatment [49]. Finally, a small trail of the treatment of HER-2 positive non-small cell lung cancer (NSCLC) patients with trastuzumab emtansine reported a rate of 3 out of 15 or 20% patients experiencing hepatotoxicity [50]. Taken together, these findings call for careful monitoring of patients receiving trastuzumab therapy so that potentially serious hepatotoxicity can be properly managed before long-term liver injury occurs. Lapatinib represents another member SB271046 HCl of the SB271046 HCl anti-HER-2 family of targeted therapies against HER-2 SB271046 HCl positive breast cancer that is additionally being explored in the treatment of other HER-2 positive cancers, similarly to trastuzumab [51]. Rabbit Polyclonal to SLC27A5 Hepatotoxicity related to lapatinib treatment occurs similarly to that of trastuzumab, but other work found an additional mechanism of liver injury in which lapatinib increases the accumulation of combination chemotherapy via inhibition of ATP-binding cassette transporters [52]. Lapatinib induced hepatotoxicity has been associated with and and a report outlining a case of lapatinib induced hepatitis that responded to therapy discontinuation exhibits the potential for lapatinib associated hepatotoxicity [53-55]. Small molecule TKIs and VEGF inhibitors Small molecule TKIs and VEGF inhibitors represent a broad category of targeted anticancer therapies used to treat wide variety of cancer types. These drugs are designed to target specific signaling molecules or cell receptors to block oncogenic pathways such as angiogenesis, growth signaling, and cell-cycle amplification and allow for patient-tailored treatment based on the mutational profile of their cancer [56,57]. While these drugs have vastly improved patient outcomes, they also are accompanied by a host of side effects including hepatotoxicity. As previously mentioned, VEGF inhibitors have a reported hepatotoxicity rate between 6.6-15.5% while TKIs have a reported hepatotoxicity rate between 25-35% highlighting the need SB271046 HCl for close monitoring and intervention by clinicians administering these treatments [24,25]. A number of case reports providing examples of TKI and VEGF inhibitor associated SB271046 HCl hepatotoxicity and their management have been published, including severe cases of fatal toxicity. Sorafenib, a.