Tumor escape and progression of HER-2/neu negative breast cancer under immune pressure

Background: Emerging data from pre-clinical and clinical studies suggest that HER-2/neu-specific T cell responses could induce HER-2/neu antigen loss in the tumor cells. These data suggest that patients with HER-2/neu negative breast cancer might have had HER-2/neu positive premalignant lesions in the past that progressed to HER-2/neu negative breast cancer under HER-2/neu-specific immune pressure. Methods: We conducted a pilot study in patients with HER-2/neu positive and HER-2/neu negative breast cancers as well as a patient with ductal carcinoma in situ (DCIS). HER-2/neu expression was determined by FISH. HER-2/ neu-specific T cell responses were determined by using IFN-g ELISA. Expression of IFN-g Ra in the tumors was determined by immunohistochemistry analysis of paraffin-embedded tissues. Results: We determined that majority of (10 of 12) patients with HER-2/neu negative breast cancer had HER-2/neuspecific IFN-g producing T cell responses which was stronger than those in patients with HER-2/neu positive tumors. Such immune responses were associated with nuclear translocation of IFN-g Ra in their tumor cells. Patient with DCIS also showed HER-2/neu-specific T cell responses. Conclusion: These data suggest that conducting retrospective studies in patients with HER-2/neu negative breast cancers and prospective studies in patients with HER-2/neu positive DCIS can determine whether HER-2/neu negative invasive carcinomas arise from HER-2/neu positive DCIS under the immune pressure.