Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer
Abstract
BACKGROUND: Women with HER2-overexpressing breast cancers have poor prognosis, and many are resistant to the HER2 monoclonal antibody trastuzumab. A subgroup of HER2-overexpressing tumors also express p95HER2, an amino terminally truncated receptor that has kinase activity. Because p95HER2 cannot bind to trastuzumab but should be responsive to the HER2 tyrosine kinase inhibitor lapatinib, we compared the sensitivity of tumors expressing p95HER2 and tumors expressing the full-length HER2 receptor to these agents. METHODS: MCF-7 and T47D breast cancer cells were stably transfected with either full-length HER2 or p95HER2. We studied the effects of trastuzumab and lapatinib on receptor signaling, cell proliferation, and the growth of xenograft tumors. A paraffin-based immunofluorescence assay was developed to study the association between p95HER2 expression and sensitivity to trastuzumab in patients with advanced breast cancer. All statistical tests were two-sided. RESULTS: Treatment of p95HER2-expressing cells with lapatinib inhibited p95HER2 phosphorylation, reduced downstream phosphorylation of Akt and mitogen-activated protein kinases, inhibited cell growth (MCF-7p95HER2 clones, lapatinib versus control, mean growth inhibition = 57.6% versus 22.6%, difference = 35%, 95% confidence interval [CI] = 22.5% to 47.3%; P<.001; T47Dp95HER2 clones, lapatinib versus control, mean growth inhibition = 36.8% versus 20%, difference = 16.8%, 95% CI = 11.3% to 22.3%, P<.001), and inhibited growth of MCF-7p95HER2 xenograft tumors (lapatinib versus control, mean = 288.8 versus 435 mm3, difference = 146.2 mm3, CI = 73.8 to 218.5 mm3, P = .002). By contrast, treatment with trastuzumab had no effect on any of these parameters. Of 46 patients with metastatic breast cancer who were treated with trastuzumab, only one of nine patients (11.1%) expressing p95HER2 responded to trastuzumab (with a partial response), whereas 19 of the 37 patients (51.4%) with tumors expressing full-length HER2 achieved either a complete (five patients) or a partial (14 patients) response (P = .029). CONCLUSIONS: Breast tumors that express p95HER2 are resistant to trastuzumab and may require alternative or additional anti-HER2-targeting strategies.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Patients with metastatic breast cancer harboring cytosolic expression of p95-HER2 exhibit a very low response rate to trastuzumab compared to those patients without p95-HER2 in their tumors.
“Patients with metastatic breast cancer harboring cytosolic expression of p95-HER2 exhibit a very low response rate to trastuzumab compared to those patients without p95-HER2 in their tumors (Scaltriti et al., 2007).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Scaltriti et al., 2007
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
New Guidelines to Evaluate the Response to Treatment in Solid Tumors
Therasse, P., Arbuck, S. G., Eisenhauer, E. A., Wanders, J., Kaplan, R. S., Rubinstein, L., Verweij, J., Van Glabbeke, M., van Oosterom, A. T., Christian, M. C., et al. (2000) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/92.3.205 · Cited by 15,660 · see citing works
Slamon, D. J., Clark, G. M., Wong, S. G., Levin, W. J., Ullrich, A., & McGuire, W. L. (1987) · Science · doi:10.1126/science.3798106 · Cited by 11,760 · see citing works
Slamon, D. J., Leyland-Jones, B., Shak, S., Fuchs, H., Paton, V., Bajamonde, A., Fleming, T., Eiermann, W., Wolter, J., Pegram, M., et al. (2001) · New England Journal of Medicine · doi:10.1056/nejm200103153441101 · Cited by 11,500 · see citing works
Self-citationStudies of the HER-2/ neu Proto-Oncogene in Human Breast and Ovarian Cancer
Slamon, D. J., Godolphin, W. J., Jones, L. A., Holt, J. A., Wong, S., Keith, D. E., Levin, W. J., Stuart, S. G., Udove, J. A., Ullrich, A., et al. (1989) · Science · doi:10.1126/science.2470152 · Cited by 6,817 · see citing works
Trastuzumab plus Adjuvant Chemotherapy for Operable HER2-Positive Breast Cancer
Romond, E. H., Perez, E. A., Bryant, J., Suman, V. J., Geyer, C. E., Davidson, N. E., Tan-Chiu, E., Martino, S., Paik, S., Kaufman, P. A., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa052122 · Cited by 5,355 · see citing works
Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer
Piccart-Gebhart, M. J., Procter, M., Leyland-Jones, B., Goldhirsch, A., Untch, M., Smith, I., Gianni, L., Baselga, J., Bell, R., Jackisch, C., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa052306 · Cited by 5,084 · see citing works
Self-citationERBB receptors and cancer: the complexity of targeted inhibitors
Hynes, N. E., & Lane, H. A. (2005) · Nature reviews. Cancer · doi:10.1038/nrc1609 · Cited by 3,313 · see citing works
Vogel, C. L., Cobleigh, M., Tripathy, D., Gutheil, J. C., Harris, L. N., Fehrenbacher, L., Slamon, D. J., Murphy, M., Novotny, W. F., Burchmore, M., et al. (2002) · Journal of Clinical Oncology · doi:10.1200/jco.20.3.719 · Cited by 3,240 · see citing works
Cobleigh, M., Vogel, C. L., Tripathy, D., Robert, N. J., Scholl, S., Fehrenbacher, L., Wolter, J. M., Paton, V. E., Shak, S., Lieberman, G., et al. (1999) · Journal of Clinical Oncology · doi:10.1200/jco.1999.17.9.2639 · Cited by 2,767 · see citing works
Humanization of an anti-p185HER2 antibody for human cancer therapy.
Carter, P., Presta, L., Gorman, C., Ridgway, J., Henner, D., Wong, W., Rowland, A., Kotts, C., Carver, M. E., & Shepard, H. (1992) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.89.10.4285 · Cited by 1,958 · see citing works
Nagata, Y., Lan, K.-H., Zhou, X., Tan, M., Esteva, F. J., Sahin, A. A., Klos, K. S., Li, P., Monia, B. P., Nguyen, N. T., et al. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.06.022 · Cited by 1,858 · see citing works
Marty, M. E., Cognetti, F., Maraninchi, D., Snyder, R., Mauriac, L., Tubiana-Hulin, M., Chan, S. Y. T., Grimes, D., Antón, A., Lluch, A. M., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.04.173 · Cited by 1,593 · see citing works
Baselga, J. M., Tripathy, D., Mendelsohn, J. M., Baughman, S. A., Benz, C. C., Dantis, L., Sklarin, N. T., Seidman, A. D., Hudis, C. A., Moore, J. L., et al. (1996) · Journal of Clinical Oncology · doi:10.1200/jco.1996.14.3.737 · Cited by 1,382 · see citing works
Self-citationHorder, & Harnett, W. L. (1941) · BMJ · doi:10.1136/bmj.1.4186.493 · Cited by 1,319 · see citing works
A Unique Structure for Epidermal Growth Factor Receptor Bound to GW572016 (Lapatinib)
Wood, E. R., Truesdale, A. T., McDonald, O. B., Yuan, D. Y., Hassell, A. M., Dickerson, S. H., Ellis, B., Pennisi, C., Horne, E., Lackey, K. E., et al. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1168 · Cited by 1,130 · see citing works
An Open-and-Shut Case? Recent Insights into the Activation of EGF/ErbB Receptors
Burgess, A. W., Cho, H., Eigenbrot, C. W., Ferguson, K. M., Garrett, T., Leahy, D. J., Lemmon, M. A., Sliwkowski, M. X., Ward, C. W., & Yokoyama, S. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00350-2 · Cited by 908 · see citing works
Insulin-Like Growth Factor-I Receptor Signaling and Resistance to Trastuzumab (Herceptin)
Lu, Y., Zi, X., Zhao, Y., Mascarenhas, D. D., & Pollak, M. (2001) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/93.24.1852 · Cited by 884 · see citing works
Molina, M. A., Codony‐Servat, J., Albanell, J., Rojo, F., Arribas, J., & Baselga, J. M. (2001) · PubMed · Cited by 766 · see citing works
Self-citationHudziak, R. M., Phillips, G. D. L., Winget, M., FENDLY, B. M., Shepard, H. M., & Ullrich, A. (1989) · Molecular and Cellular Biology · doi:10.1128/mcb.9.3.1165-1172.1989 · Cited by 750 · see citing works
Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu
Benz, C. C., Scott, G. K., Sarup, J. C., Johnson, R. M., Tripathy, D., Coronado, E. B., Shepard, H. M., & Osborne, C. K. (1992) · Breast Cancer Research and Treatment · doi:10.1007/bf01961241 · Cited by 749 · see citing works
Burris, H. A., Hurwitz, H. I., Dees, E. C., Dowlati, A., Blackwell, K., O’Neil, B. H., Marcom, P. K., Ellis, M. J., Overmoyer, B. A., Jones, S. F., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.16.584 · Cited by 619 · see citing works
Targeting Tyrosine Kinases in Cancer: The Second Wave
Baselga, J. M. (2006) · Science · doi:10.1126/science.1125951 · Cited by 478 · see citing works
Self-citationBaselga, J., Carbonell, X., Castañeda-Soto, N.-J., et al. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.01.014 · Cited by 427 · see citing works
Self-citationRees, S., Coote, J., Stables, J., Goodson, S., Harris, S., & Lee, M. (1996) · BioTechniques · doi:10.2144/96201st05 · Cited by 299 · see citing works
Mechanism of action of trastuzumab and scientific update
Baselga, J. M., Albanell, J., Molina, M. A., & Arribas, J. (2001) · Seminars in Oncology · doi:10.1016/s0093-7754(01)90276-3 · Cited by 259 · see citing works
Self-citationChristianson, T. A., Doherty, J. K., Lin, Y.-J., et al. (1998) · PubMed · Cited by 253 · see citing works
Codony‐Servat, J., Albanell, J., López-Talavera, J. C., et al. (1999) · PubMed · Cited by 238 · see citing works
Molina‐Vila, M. Á., Sáez, R., Ramsey, E. E., et al. (2002) · PubMed · Cited by 235 · see citing works
Biosynthesis of tumorigenic HER2 C-terminal fragments by alternative initiation of translation
Anido, J., Scaltriti, M., Bech Serra, J. J., Josefat, B. S., Rojo Todo, F., Baselga, J., & Arribas, J. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601191 · Cited by 231 · see citing works
Self-citationp95HER-2 Predicts Worse Outcome in Patients with HER-2-Positive Breast Cancer
Sáez, R., Molina‐Vila, M. Á., Ramsey, E. E., et al. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-1807 · Cited by 218 · see citing works
Segatto, O., King, C. R., Pierce, J. H., Fiore, P. P. D., & Aaronson, S. A. (1988) · Molecular and Cellular Biology · doi:10.1128/mcb.8.12.5570 · Cited by 186 · see citing works
Early tumor response to Hsp90 therapy using HER2 PET: comparison with 18F-FDG PET.
Smith-Jones, P. M., Solit, D. B., Afroze, F., Rosen, N. X., & Larson, S. M. (2006) · PubMed · Cited by 173 · see citing works
Scott, G. K., Robles, R., Park, J. W., Montgomery, P. A., Daniel, J., Holmes, W. E., Lee, J., Keller, G. A., Li, W. L., & FENDLY, B. M. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.4.2247 · Cited by 158 · see citing works
Akiyama, T., Matsuda, S., Namba, Y., Saito, T., Toyoshima, K., & Yamamoto, T. S. (1991) · Molecular and Cellular Biology · doi:10.1128/mcb.11.2.833 · Cited by 126 · see citing works
A Phase I Study of Cetuximab/Paclitaxel in Patients with Advanced-Stage Breast Cancer
Modi, S., D’Andrea, G. M., Norton, L., et al. (2006) · Clinical Breast Cancer · doi:10.3816/cbc.2006.n.040 · Cited by 98 · see citing works
Molecular approach to breast cancer treatment
Yarden, Y., Baselga, J. M., & Miles, D. W. (2004) · Seminars in Oncology · doi:10.1053/j.seminoncol.2004.07.016 · Cited by 77 · see citing works
Self-citationWong, K., Fracasso, P. M., Bukowski, R. M., Munster, P. N., Lynch, T. J., Abbas, R., Quinn, S. E., Zacharchuk, C., & Burris, H. A. (2006) · Journal of Clinical Oncology · doi:10.1200/jco.2006.24.18_suppl.3018 · Cited by 57 · see citing works
Egeblad, M., Mortensen, O. H., & Jäättelä, M. (2001) · International Journal of Cancer · doi:10.1002/ijc.1459 · Cited by 38 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Slamon D , Eiermann W , Robert N , Pienkowski T , Martin M , Pawlicki M , et al . Phase III randomized trial comparing doxorubicin and cyclophos- phamide followed by docetaxel (ACT) with doxorubicin and cyclophos- phamide followed by docetaxel and trastuzumab (ACTH) with docetaxel, carboplatin and trastuzumab (TCH) in HER-2 positive early breast cancer patients: BCIRG 006 study . 28th Annual San Antonio Breast Cancer Symposium (December 8-11, 2005):Abstract 1.
Cited by
Sorted by citations
ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics
Arteaga, C. L., & Engelman, J. A. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.02.025 · Cited by 1,048 · see citing works
Solca, F., Dahl, G., Zoephel, A., Bader, G., Sanderson, M., Klein, C., Kraemer, O., Himmelsbach, F., Haaksma, E., & Adolf, G. R. (2012) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.197756 · Cited by 865 · see citing works
EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance
Uribe, M. L., Marrocco, I., & Yarden, Y. (2021) · Cancers · doi:10.3390/cancers13112748 · Cited by 604 · see citing works
Zhang, S., Huang, W.-C., Li, P., Guo, H., Poh, S.-B., Brady, S. W., Xiong, Y., Tseng, L.-M., Li, S.-H., Ding, Z., et al. (2011) · Nature Medicine · doi:10.1038/nm.2309 · Cited by 515 · see citing works
Eichhorn, P. J. A., Gili, M., Scaltriti, M., Serra, V., Guzman, M., Nijkamp, W., Beijersbergen, R. L., Valero, V., Seoane, J., Bernards, R., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-1740 · Cited by 499 · see citing works
Self-citationScaltriti, M., Eichhorn, P. J., Cortés, J., Prudkin, L., Aura, C., Jiménez, J., Chandarlapaty, S., Serra, V., Prat, A., Ibrahim, Y. H., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1014835108 · Cited by 337 · see citing works
Self-citationMitra, D., Brumlik, M. J., Okamgba, S. U., Zhu, Y., Duplessis, T. T., Parvani, J. G., Lesko, S. M., Brogi, E., & Jones, F. E. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0295 · Cited by 204 · see citing works
Scaltriti, M., Chandarlapaty, S., Prudkin, L., Aura, C., Jimenez, J., Angelini, P. D., Sánchez, G., Guzman, M., Parra, J. L., Ellis, C., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-3407 · Cited by 151 · see citing works
Self-citationMinuti, G., Cappuzzo, F., Duchnowska, R., Jassem, J., Fabi, A., O’Brien, T., Mendoza, A. D., Landi, L., Biernat, W., Czartoryska-Arłukowicz, B., et al. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.335 · Cited by 127 · see citing works
NSCLC and HER2: between lights and shadows
Ricciardi, G. R. R., Russo, A., Franchina, T., Ferraro, G., Zanghì, M., Picone, A., Scimone, A., & Adamo, V. (2014) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000379 · Cited by 78 · see citing works
Surrogate markers for targeted therapy-based treatment activity and efficacy
Bianchini, G., & Gianni, L. (2011) · JNCI Monographs · doi:10.1093/jncimonographs/lgr024 · Cited by 2 · see citing works
- Authors
- Scaltriti, M., Rojo, F., Ocana, A., Anido, J., Guzman, M., Cortes, J., Di Cosimo, S., Matias-Guiu, X., Ramon y Cajal, S., Arribas, J., & Baselga, J.
- Affiliations
- Universitat Autònoma de Barcelona (ES)
- Venue
- JNCI Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-04-17
- Volume
- 99
- Issue
- 8
- Pages
- 628-638
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- OpenAlex
- W2172265576
- Cited by
- 895
- References
- 38
- Citations by year
- 2026: 34 · 2025: 36 · 2024: 40 · 2023: 42 · 2022: 32 · 2021: 29 · 2020: 33 · 2019: 36 · 2018: 39 · 2017: 39 · 2016: 35 · 2015: 50 · 2014: 66 · 2013: 58 · 2012: 72
- FWCI
- 31.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P30CA008748)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- p95HER2, HER2 receptor, HER2-positive breast cancer, trastuzumab resistance, lapatinib, HER2 tyrosine kinase inhibitor, truncated receptor, Akt phosphorylation, MAPK signaling, xenograft tumor growth, immunofluorescence assay, metastatic breast cancer, MCF-7 cells
- MeSH terms
- Trastuzumab, Lapatinib, Animals, Antibodies, Monoclonal, Antineoplastic Agents, Breast Neoplasms, Cell Cycle, Cell Division, Cloning, Molecular, Female, Genetic Vectors, Humans, Mice, Nude, Quinazolines, Transfection, Transplantation, Heterologous, Signal Transduction, Sequence Deletion, DNA, Complementary, Erb-b2 Receptor Tyrosine Kinases, Genes, erbB-2, Cell Line, Tumor, Mice, Antibodies, Monoclonal, Humanized
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
