PDF - 39K, The ER, PR, and HER2 (ERBB2) status was determined by standardized immunohistochemical staining and pathological analysis at Spectrum Health. ER, PR, and HER2 scores are based on IHC guidelines recommended by the ASCO/CAP.

Abstract Breast cancer displays significant intratumoral heterogeneity, which has been shown to have a substantial impact on both innate and acquired resistance to tyrosine kinase inhibitors. The heterogeneous expression of multiple receptor tyrosine kinases (RTK) in cancers supports tumor signaling robustness and plays a significant role in resistance to targeted inhibition. Recent studies have revealed interactions between the MET receptor and the ERBB receptor family in the therapeutic resistance of several cancers. In this study, the relationship between MET expression/activity and the expression/activity of the ERBB receptor family in human breast cancer was interrogated. Importantly, a significant percentage of ERBB2+ tumors coexpressing MET and ERBB2 were observed and displayed significant heterogeneity with subpopulations of cells that are MET−/ERBB2+, MET+/ERBB2−, and MET+/ERBB2+. In a MET+/ERBB2+ breast cancer cell line, MET depletion resulted in increased ERBB2 activation, and conversely, ERBB2 depletion resulted in increased MET activation. Neither EGFR nor ERBB3 compensated for MET or ERBB2 knockdown. The loss of either MET or ERBB2 led to a decrease in PI3K/AKT signaling and increased dependency on MAPK. These data show that a subset of ERBB2+ breast cancers express MET and contain MET+/ERBB2+ subpopulations. Moreover, analysis of RTK activation during ERBB2 knockdown indicated that MET signaling is a compensatory pathway of resistance. Implications: ERBB2+ breast cancers with MET+/ERBB2+ subpopulations may have an innate resistance to ERBB2 inhibition and may benefit from combined MET and ERBB2 inhibition. Mol Cancer Res; 11(9); 1112–21. ©2013 AACR.

Breast cancer displays significant intratumoral heterogeneity, which has been shown to have a substantial impact on both innate and acquired resistance to tyrosine kinase inhibitors. The heterogeneous expression of multiple receptor tyrosine kinases (RTK) in cancers supports tumor signaling robustness and plays a significant role in resistance to targeted inhibition. Recent studies have revealed interactions between the MET receptor and the ERBB receptor family in the therapeutic resistance of several cancers. In this study, the relationship between MET expression/activity and the expression/activity of the ERBB receptor family in human breast cancer was interrogated. Importantly, a significant percentage of ERBB2þ tumors coexpressing MET and ERBB2 were observed and displayed significant heterogeneity with subpopulations of cells that are MET / ERBB2þ, METþ/ERBB2 , and METþ/ERBB2þ. In a METþ/ERBB2þ breast cancer cell line, MET depletion resulted in increased ERBB2 activation, and conversely, ERBB2 depletion resulted in increased MET activation. Neither EGFR nor ERBB3 compensated for MET or ERBB2 knockdown. The loss of either MET or ERBB2 led to a decrease in PI3K/AKT signaling and increased dependency on MAPK. These data show that a subset of ERBB2þ breast cancers express MET and contain METþ/ERBB2þ subpopulations. Moreover, analysis of RTK activation during ERBB2 knockdown indicated that MET signaling is a compensatory pathway of resistance. Implications: ERBB2þ breast cancers with METþ/ERBB2þ subpopulations may have an innate resistance to ERBB2 inhibition andmay benefit from combinedMET and ERBB2 inhibition.Mol Cancer Res; 11(9); 1112–21.

1 Background: The U.S. Preventative Services Task Force (USPSTF) revised their breast cancer screening recommendations in 2009 changing their stance on age and frequency of mammography screening to biannual exams starting at age 50. The purpose of this study is to analyze data from a statewide breast cancer registry managed by the Michigan Breast Oncology Quality Initiative (MiBOQI) to determine the impact of these new recommendations on diagnosing and treating breast cancer. Methods: De-identified data were collected on women participating in the MiBOQI registry at seventeen statewide institutions from 2006-2009. Data included method of detection, cancer stage, age at detection, treatment type, and patient demographics. Participants were stratified based on age, and data analyzed using NCSS software (chi-square and t-tests). Results:5903 women with breast cancer with an average age at diagnosis of 59.4 years were included. 65.5% of breast cancers were detected via mammography, 29.8% by palpation, and 4.7% by other methods. In women under 50 years of age, cancers were detected by mammography in 48.3% (69.3% >50yr) and by palpation in 46.1% (24.1% >50yr). Patients with palpable presentations were younger (55.8 yr vs. 61.2 yr; p <0.001). Cancers with a palpable presentation were diagnosed at higher stages (50.0% stage II) than with mammography (52.5% stage I; p<0.001). Breast conservation surgery occurred more frequently than mastectomy (palpation 54.2%; mammography 72.9%, p<0.001) but cancers detected through palpation were more likely to undergo mastectomy procedures. Conclusions: Results of this study validate the importance of annual screening mammography in women older than 50 years, and women aged 40 to 49 years recently omitted from screening guidelines. There was an increased prevalence of palpation for the method of detection in women less than 50 years of age. If screening mammography is omitted in this group, cancers when detected may be of a more advanced stage and result in more mastectomies. This study also supports the use of palpation as a method of detection despite recent recommendations against teaching self breast exams by USPSTF.

6039 Background: A 21-gene RT-PCR assay (the assay) has been recommended to predict the risk of recurrence and likelihood of adjuvant chemotherapy (AC) benefit in a subgroup of newly diagnosed pati...