HER2/neu-directed therapy for biliary tract cancer

Milind Javle, Chaitanya Churi, HyunSeon C Kang, Rachna Shroff, Filip Janku, Rakesh Surapaneni, Mingxin Zuo, Christian Barrera, Humaid Alshamsi, Sunil Krishnan, Lopa Mishra, Robert A Wolff, Ahmed O Kaseb, Melanie B Thomas, Abby B Siegel, Milind Javle, Chaitanya Churi, HyunSeon C Kang, Rachna Shroff, Filip Janku, Rakesh Surapaneni, Mingxin Zuo, Christian Barrera, Humaid Alshamsi, Sunil Krishnan, Lopa Mishra, Robert A Wolff, Ahmed O Kaseb, Melanie B Thomas, Abby B Siegel

Abstract

Background: Biliary cancers are highly aggressive tumors that are often diagnosed an advanced disease stage and have a poor outcome with systemic therapy. Recent efforts towards molecular characterization have identified a subset of biliary patients that have HER2/neu amplification or mutation. HER2/neu amplification is associated with response to HER2/neu-directed therapy in breast and gastric cancers. However, the efficacy of HER2/neu-targeted therapy in biliary cancers is unknown.

Patients and methods: We retrospectively reviewed cases of advanced gallbladder cancer and cholangiocarcinoma with HER2/neu genetic aberrations or protein overexpression who received HER2/neu-directed therapy between 2007 and 2014. Clinical data were retrieved from medical records, and imaging studies were independently reviewed.

Results: Nine patients with gallbladder cancer and five patients with cholangiocarcinoma had received HER2/neu-directed therapy (trastuzumab, lapatinib, or pertuzumab) during the study period. In the gallbladder cancer group, HER2/neu gene amplification or overexpression was detected in eight cases. These patients experienced disease stability (n = 3), partial response (n = 4), or complete response (n = 1) with HER2/neu-directed therapy. One patient had HER2/neu mutation and experienced a mixed response after lapatinib therapy. The duration of response varied from 8+ to 168 weeks (median 40 weeks), and three patients are still on therapy. One patient developed HER2/neu amplification as a secondary event after FGFR-directed therapy for FGF3-TACC3 gene fusion. The cholangiocarcinoma cases treated in this series had a higher proportion of HER2/neu mutations, and no radiological responses were seen in these patients despite HER2/neu-directed therapy.

Conclusions: HER2/neu blockade is a promising treatment strategy for gallbladder cancer patients with gene amplification and deserves further exploration in a multi-center study.

Figures

Fig. 1
Fig. 1
A 61-year-old female with gallbladder carcinoma invading the liver. Axial contrast-enhanced CT images demonstrate a a 2.4 × 1.3 cm polypoid mass (small arrowheads) in the gallbladder neck causing gallbladder obstruction. The mass directly invades the liver, with a 2.9 × 3.9 cm liver mass (arrow). b After 3 months of trastuzumab and FOLFOX, the polypoid gallbladder mass is no longer visualized, and the liver mass decreased to 1.2 × 1.1 cm (arrow). The patient was then treated with en bloc cholecystectomy and extended right hepatectomy, followed by capecitabine and trastuzumab for 7 months. c After 6 months of observation (14 months after surgery), the patient had small volume recurrence to retroperitoneal lymph nodes (large arrowheads). After treatment with FOXFOX and trastuzumab for 3 months, d a previously seen 1-cm retroperitoneal lymph node is nearly imperceptible
Fig. 2
Fig. 2
A 64-year-old female with recurrent gallbladder carcinoma. Axial contrast-enhanced CT images demonstrate a a 1.2-cm nodule (arrowhead) in the gallbladder fossa adjacent to the hepatic flexure and b a 1.7-cm nodule (arrow) in the portocaval region. Both nodules were new from the postoperative scan (following resection of recurrent tumor in the gallbladder fossa), in keeping with recurrence. c, d Thirteen months later, both nodules are stable after treatment with trastuzumab
Fig. 3
Fig. 3
A 62-year-old female with recurrent metastatic gallbladder carcinoma with carcinomatosis. Axial contrast-enhanced CT images demonstrate a enhancing perihepatic nodules (arrowheads), b a 4.8-cm metastasis destroying the sternum (arrow), and c a 1.8-cm lung metastasis (circle). After 3 months of trastuzumab, d the perihepatic nodules are no longer visualized. e The sternum has become sclerotic with decreased size of the metastasis (arrow), and f the lung metastasis has undergone cavitation (circle).
Fig. 4
Fig. 4
A 45-year-old female with metastatic gallbladder carcinoma. Axial contrast-enhanced CT images demonstrate a a 1.5-cm liver metastasis (arrowheads) and b prominent soft tissue (arrows) in the cholecystectomy bed abutting the liver. After 2 months of treatment with trastuzumab, c the liver metastasis is barely visible at 4 mm, and d the soft tissue mass in the resection bed, representing recurrent tumor, is decreased. She was stable for an additional 5 months, then had recurrence in the resection bed
Fig. 5
Fig. 5
A 73-year-old female with metastatic retroperitoneal lymphadenopathy from gallbladder carcinoma. Axial contrast-enhanced CT images demonstrate a a 1.9-cm lymph node (arrowheads) posterior to the left renal vein. After 2 months of trastuzumab and pertuzumab, b the lymph node decreased to 1.2 cm. c Her CA 19-9 response to HER2/neu inhibition after prior FGFR inhibitor therapy

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Source: PubMed

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