Overcoming Trastuzumab Resistance in HER2+ Esophagogastric Cancer


By Yelena Y. Janjigian, MD

Summer 2013 — Esophagogastric cancer is the second most common cause of cancer-related death worldwide and represents an enormous global health burden.

Trastuzumab is the first targeted agent approved by the US Food and Drug Administration for the treatment of HER2-positive esophagogastric cancer. (1)

Unfortunately, despite an initial response to trastuzumab, most patients develop resistance to the drug and experience cancer progression. Until now, no other HER2-directed therapy has produced a benefit in these patients. At Memorial Sloan Kettering, we are working to expand our understanding of the molecular basis for trastuzumab resistance by bringing together investigators in gastrointestinal oncology, pathology, and the genomic analysis of HER2+ breast cancer.

Our program is now poised to shed light on trastuzumab resistance in esophagogastric cancer.

In breast cancer, trastuzumab resistance is often associated with ongoing dependence on HER2 signaling. As an example, increased expression of a truncated form of HER2 (p95-HER2) lacking the extracellular domain to which trastuzumab binds results in trastuzumab resistance with retained HER2 dependence.

Potential mechanisms of trastuzumab resistance suggested by preclinical studies include expression of p95-HER2, activation of parallel signaling pathways (such as MET or insulin-like growth factor-1 receptor [IGF-1R]), or downstream activation of the PI3K-AKT-mTOR pathway as a result of loss of PTEN or mutational activation of PI3KCA.

Memorial Sloan Kettering preliminary molecular data in patients with breast cancer confirm an increase in PTEN/PI3K alterations in trastuzumab-refractory breast cancers compared to trastuzumab-naive cancers. Analyses of primary esophagogastric adenocarcinomas demonstrate PTEN deletion in approximately 5 percent of cases, (2) HER2 mutations in approximately 5 percent of cases, and mutation of PI3KCA in approximately 7 percent of cases. (3), (4), (5)

Whether these or other lesions occur in trastuzumab-refractory tumors, and what their significance is in this clinical context, is unknown. At Memorial Sloan Kettering, we are analyzing the progressive, trastuzumab-resistant HER2+ esophagogastric tumors compared with archival pretreatment tumors from individual patients to elucidate the genetic drivers of trastuzumab resistance in esophagogastric cancer.

Our lab is working on generating and characterizing patient-derived xenograft (PDX) models of this disease state to identify and validate rational second-line treatment strategies. One of these treatments is afatinib, a new drug currently in development for treatment of lung cancer and HER2+ breast cancer. Afatinib is well tolerated in patients, with side effects limited to diarrhea and acne-like rash. In clinical trials, patients with HER2+ breast cancer with trastuzumab-resistant tumors experienced dramatic tumor shrinkage and stabilization with afatinib treatment.

Laboratory experiments in PDXs of HER2+ esophagogastric cancer show that afatinib is very effective for this disease. (6) Based on these results, a phase II study of afatinib in HER2+ trastuzumab refractory esophagogastric cancer is now under way at Memorial Sloan Kettering.

Moreover, we are developing functional PET imaging techniques to stage and monitor treatment response in HER2+ esophagogastric cancer in collaboration with the Chief of the Radiochemistry and Imaging Sciences Service, Jason Lewis. Heterogeneity of HER2 expression within primary tumors and metastasis is a particular challenge and may contribute to trastuzumab resistance. (7)

In addition, the bio-distribution of trastuzumab varies in each patient and is heavily impacted by the extent of tumor load, which may contribute to variations in patient responses. (8), (9), (10)89Zr-trastuzumab PET may thus help elucidate the molecular basis of resistance to trastuzumab in esophagogastric cancer and facilitate the development of an optimal dose and schedule of HER2-targeted agents tailored to individual tumor burden and biology.

Memorial Sloan Kettering preclinical data demonstrate that 89Zr-trastuzumab but not conventional FDG PET can accurately and noninvasively show changes in HER2 expression and tumor size in HER2-positive esophagogastric xenografts treated with afatinib (Fig 1). A phase I clinical study of 89Zr-trastuzumab PET in patients with HER2-positive esophagogastric cancer will be opening shortly.

In summary, HER2-directed therapies hold hope and promise for a subset of patients with esophagogastric cancer. Synergy between the basic research skills and clinical expertise of the collaborating groups is a distinguishing feature of this research, which is supported by the American Society of Clinical Oncology’s Conquer Cancer Foundation.

  1. Bang YJ, Van Cutsem E, Feyereislova A, et al: Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet, 2010
  2. Mina S, Bohn BA, Simon R, et al: PTEN deletion is rare but often homogeneous in gastric cancer. J Clin Pathol, 2012
  3. Lee JW, Soung YH, Seo SH, et al: Somatic mutations of ERBB2 kinase domain in gastric, colorectal, and breast carcinomas. Clin Cancer Res 12:57-61, 2006
  4. Yang L, Kuang LG, Zheng HC, et al: PTEN encoding product: a marker for tumorigenesis and progression of gastric carcinoma. World J Gastroenterol 9:35-9, 2003
  5. Im SA, Lee KE, Nam E, et al: Potential prognostic significance of p185(HER2) overexpression with loss of PTEN expression in gastric carcinomas. Tumori 91:513-21, 2005
  6. Janjigian YY, Viola-Villegas N, Holland JP, et al: Monitoring Afatinib Treatment in HER2-Positive Gastric Cancer with 18F-FDG and 89Zr-Trastuzumab PET. J Nucl Med, 2013
  7. Hofmann M, Stoss O, Shi D, et al: Assessment of a HER2 scoring system for gastric cancer: Results from a validation study. Histopathology 52:797-805, 2008
  8. Leyland-Jones B, Colomer R, Trudeau ME, et al: Intensive loading dose of trastuzumab achieves higher-than-steady-state serum concentrations and is well tolerated. J Clin Oncol 28:960-6, 2010
  9. Oude Munnink TH, Dijkers EC, Netters SJ, et al: Trastuzumab pharmacokinetics influenced by extent human epidermal growth factor receptor 2-positive tumor load. J Clin Oncol 28:e355-6; author reply e357, 2010
  10. Dijkers EC, Oude Munnink TH, Kosterink JG, et al: Biodistribution of 89Zr-trastuzumab and PET Imaging of HER2-Positive Lesions in Patients With Metastatic Breast Cancer. Clin Pharmacol Ther 87:586-592, 2010