HER2 intratumoral heterogeneity is independently associated with incomplete response to anti-HER2 neoadjuvant chemotherapy in HER2-positive breast carcinoma

Hou, Yanjun; Nitta, Hiroaki; Wei, Lai; Banks, Peter M.; Portier, Bryce P.; Parwani, Anil V.; Li, Zaibo

doi:10.1007/s10549-017-4453-8

Cited by 76 publications

(56 citation statements)

References 41 publications

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“…Although our analysis is limited by a small number of cases, these results are in line with recent data. 23 , 24 When pCR and near-pCR categories were grouped together, the response rates in double-equivocal carcinomas reached 40%; however, we cannot rule out that this was due to the beneficial effect of chemotherapy, as this rate was not significantly different from the rates accrued in a cohort of ER-positive/HER2-negative patients treated with chemotherapy only. It should be emphasized that this is a hypothesis-generating study and that larger studies comparing patients who received the same chemotherapy regimens +/− trastuzumab treatment are warranted to ascertain the real impact of anti-HER2 therapy in this specific subset of breast carcinomas.…”

Section: Discussionmentioning

confidence: 86%

The Dilemma of HER2 Double-equivocal Breast Carcinomas

Marchiò

Dell’Orto

Annaratone³

et al. 2018

American Journal of Surgical Pathology

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Section: Discussionmentioning

confidence: 86%

The Dilemma of HER2 Double-equivocal Breast Carcinomas

Marchiò

Dell’Orto

Annaratone³

et al. 2018

American Journal of Surgical Pathology

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“…In a subsequent study, Lee et al [21] reported that cases with HER2 regional heterogeneity showed a decreased disease-free survival rate compared to those without heterogeneity in the hormone receptor-positive subgroup of breast cancer patients treated with adjuvant trastuzumab. In a neoadjuvant setting, intratumoral HER2 heterogeneity was also found to be associated with incomplete response to anti-HER2 chemotherapy [22].…”

Section: Complicating Factors For Her2 Interpretationmentioning

confidence: 99%

HER2 status in breast cancer: changes in guidelines and complicating factors for interpretation

Ahn

Woo

Lee

et al. 2020

J Pathol Transl Med

169

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/ by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Human epidermal growth factor receptor 2 (HER2) is a protooncogene that encodes epidermal growth factor receptor with tyrosine kinase activity, located on chromosome 17 at q21. In breast cancers, HER2 gene is amplified in 15%-20% of invasive breast cancers and its amplification is closely linked to HER2 protein overexpression [1,2]. HER2 amplification is a poor prognostic factor associated with a high rate of recurrence and mortality, and is a predictive factor for response to anthracyclinebased chemotherapies in patients with breast cancer [1,2]. Most importantly, it is a sole predictive marker for treatment benefits from HER2-targeting agents such as trastuzumab, lapatinib, and pertuzumab. As HER2-targeted therapy is exclusively effective in HER2-overexpressed and/or HER2-amplified breast cancers, precise assessment of HER2 status is an essential step for treatment of breast cancer. In this review, we focused on changes in the American Society of Clinical Oncology (ASCO)/ College of American Pathologists (CAP) guidelines on HER2 interpretation and some pitfalls in the interpretation of HER2 status in breast cancers. METHODS OF HER2 TESTINGCurrently, immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and chromogenic in situ hybridization (CISH) including silver in situ hybridization (SISH) are regarded as standard methods for determination of HER2 status in breast cancer, and some of them have been approved by the U.S. Food and Drug Administration (FDA) for HER2 testing in breast cancer since 1998.Although HER2 status can be directly tested by in situ hybridization (ISH), many laboratories have adopted IHC as a screening test, and FISH as a confirmation test for HER2 IHC equivocal cases, considering higher failure rate, longer procedure time and higher reagent cost of FISH, compared to that of IHC. Moreover, Human epidermal growth factor receptor 2 (HER2) protein overexpression and/or HER2 gene amplification is found in about 20% of invasive breast cancers. It is a sole predictive marker for treatment benefits from HER2 targeted therapy and thus, HER2 testing is a routine practice for newly diagnosed breast cancer in pathology. Currently, HER2 immunohistochemistry (IHC) is used for a screening test, and in situ hybridization is used as a confirmation test for HER2 IHC equivocal cases. Since the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines on HER2 testing was first released in 2007, it has been updated to provide clear instructions for HER2 testing and accurate determination of HER2 status in breast cancer. During HER2 interpretation, some pitfalls such as intratumoral HER2 heterogeneity and increase in chromosome enumeration probe 17 signals m...

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“…ERBB2 was particularly highly expressed in PUC-GBC1 and PUC-GBC2, and showed a somewhat lower expression in PUC-GBC3. This is not an unexpected finding considering that intratumor heterogeneity is a common event in cancer, and genetic heterogeneity of HER2 has been reported for other tumors [82][83][84][85][86][87][88]. For instance, focal or patchy positivity of HER2 is a pattern encountered in primary gastric tumors, which is consequence of the intratumor heterogeneity and could explain discordances observed in HER2 status between the primary tumor and metastatic sites [82,85].…”

Section: Discussionmentioning

confidence: 50%

Functional and genomic characterization of three novel cell lines derived from a metastatic gallbladder cancer tumor

et al. 2020

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Background: Gallbladder cancer (GBC) is the most common tumor of the biliary tract. The incidence of GBC shows a large geographic variability, being particularly frequent in Native American populations. In Chile, GBC represents the second cause of cancer-related death among women. We describe here the establishment of three novel cell lines derived from the ascitic fluid of a Chilean GBC patient, who presented 46% European, 36% Mapuche, 12% Aymara and 6% African ancestry.Results: After immunocytochemical staining of the primary cell culture, we isolated and comprehensively characterized three independent clones (PUC-GBC1, PUC-GBC2 and PUC-GBC3) by short tandem repeat DNA profiling and RNA sequencing as well as karyotype, doubling time, chemosensitivity, in vitro migration capability and in vivo tumorigenicity assay. Primary culture cells showed high expression of CK7, CK19, CA 19-9, MUC1 and MUC16, and negative expression of mesothelial markers. The three isolated clones displayed an epithelial phenotype and an abnormal structure and number of chromosomes. RNA sequencing confirmed the increased expression of cytokeratin and mucin genes, and also of TP53 and ERBB2 with some differences among the three cells lines, and revealed a novel exonic mutation in NF1. The PUC-GBC3 clone was the most aggressive according to histopathological features and the tumorigenic capacity in NSG mice. Conclusions:The first cell lines established from a Chilean GBC patient represent a new model for studying GBC in patients of Native American descent.

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HER2 intratumoral heterogeneity is independently associated with incomplete response to anti-HER2 neoadjuvant chemotherapy in HER2-positive breast carcinoma

Abstract: HER2 ITH analyses conducted with GPA method revealed that HER2 ITH is an independent factor predicting incomplete response to anti-HER2 neoadjuvant chemotherapy.

Cited by 76 publications

References 41 publications

The Dilemma of HER2 Double-equivocal Breast Carcinomas

The Dilemma of HER2 Double-equivocal Breast Carcinomas

HER2 status in breast cancer: changes in guidelines and complicating factors for interpretation

Functional and genomic characterization of three novel cell lines derived from a metastatic gallbladder cancer tumor

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