Intratumoral Heterogeneity and Immune Response Indicators to Predict Overall Survival in a Retrospective Study of HER2-Borderline (IHC 2+) Breast Cancer Patients
Breast cancer (BC) categorized as human epidermal growth factor receptor 2 (HER2) borderline [2+ by immunohistochemistry (IHC 2+)] presents challenges for the testing, frequently obscured by intratumoral heterogeneity (ITH). This leads to difficulties in therapy decisions. We aimed to establish prog...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:73d1a54944394a3f9f244347fdfc92a22021-11-11T06:34:46ZIntratumoral Heterogeneity and Immune Response Indicators to Predict Overall Survival in a Retrospective Study of HER2-Borderline (IHC 2+) Breast Cancer Patients2234-943X10.3389/fonc.2021.774088https://doaj.org/article/73d1a54944394a3f9f244347fdfc92a22021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.774088/fullhttps://doaj.org/toc/2234-943XBreast cancer (BC) categorized as human epidermal growth factor receptor 2 (HER2) borderline [2+ by immunohistochemistry (IHC 2+)] presents challenges for the testing, frequently obscured by intratumoral heterogeneity (ITH). This leads to difficulties in therapy decisions. We aimed to establish prognostic models of overall survival (OS) of these patients, which take into account spatial aspects of ITH and tumor microenvironment by using hexagonal tiling analytics of digital image analysis (DIA). In particular, we assessed the prognostic value of Immunogradient indicators at the tumor–stroma interface zone (IZ) as a feature of antitumor immune response. Surgical excision samples stained for estrogen receptor (ER), progesterone receptor (PR), Ki67, HER2, and CD8 from 275 patients with HER2 IHC 2+ invasive ductal BC were used in the study. DIA outputs were subsampled by HexT for ITH quantification and tumor microenvironment extraction for Immunogradient indicators. Multiple Cox regression revealed HER2 membrane completeness (HER2 MC) (HR: 0.18, p = 0.0007), its spatial entropy (HR: 0.37, p = 0.0341), and ER contrast (HR: 0.21, p = 0.0449) as independent predictors of better OS, with worse OS predicted by pT status (HR: 6.04, p = 0.0014) in the HER2 non-amplified patients. In the HER2-amplified patients, HER2 MC contrast (HR: 0.35, p = 0.0367) and CEP17 copy number (HR: 0.19, p = 0.0035) were independent predictors of better OS along with worse OS predicted by pN status (HR: 4.75, p = 0.0018). In the non-amplified tumors, three Immunogradient indicators provided the independent prognostic value: CD8 density in the tumor aspect of the IZ and CD8 center of mass were associated with better OS (HR: 0.23, p = 0.0079 and 0.14, p = 0.0014, respectively), and CD8 density variance along the tumor edge predicted worse OS (HR: 9.45, p = 0.0002). Combining these three computational indicators of the CD8 cell spatial distribution within the tumor microenvironment augmented prognostic stratification of the patients. In the HER2-amplified group, CD8 cell density in the tumor aspect of the IZ was the only independent immune response feature to predict better OS (HR: 0.22, p = 0.0047). In conclusion, we present novel prognostic models, based on computational ITH and Immunogradient indicators of the IHC biomarkers, in HER2 IHC 2+ BC patients.Gedmante RadziuvieneGedmante RadziuvieneAllan RasmussonAllan RasmussonRenaldas AugulisRenaldas AugulisRuta Barbora GrineviciuteDovile ZilenaiteDovile ZilenaiteAida LaurinavicieneAida LaurinavicieneValerijus OstapenkoArvydas LaurinaviciusArvydas LaurinaviciusFrontiers Media S.A.articleHER2breast cancerintratumoral heterogeneityCD8immune responsetumor microenvironmentNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
HER2 breast cancer intratumoral heterogeneity CD8 immune response tumor microenvironment Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
| spellingShingle |
HER2 breast cancer intratumoral heterogeneity CD8 immune response tumor microenvironment Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Gedmante Radziuviene Gedmante Radziuviene Allan Rasmusson Allan Rasmusson Renaldas Augulis Renaldas Augulis Ruta Barbora Grineviciute Dovile Zilenaite Dovile Zilenaite Aida Laurinaviciene Aida Laurinaviciene Valerijus Ostapenko Arvydas Laurinavicius Arvydas Laurinavicius Intratumoral Heterogeneity and Immune Response Indicators to Predict Overall Survival in a Retrospective Study of HER2-Borderline (IHC 2+) Breast Cancer Patients |
| description |
Breast cancer (BC) categorized as human epidermal growth factor receptor 2 (HER2) borderline [2+ by immunohistochemistry (IHC 2+)] presents challenges for the testing, frequently obscured by intratumoral heterogeneity (ITH). This leads to difficulties in therapy decisions. We aimed to establish prognostic models of overall survival (OS) of these patients, which take into account spatial aspects of ITH and tumor microenvironment by using hexagonal tiling analytics of digital image analysis (DIA). In particular, we assessed the prognostic value of Immunogradient indicators at the tumor–stroma interface zone (IZ) as a feature of antitumor immune response. Surgical excision samples stained for estrogen receptor (ER), progesterone receptor (PR), Ki67, HER2, and CD8 from 275 patients with HER2 IHC 2+ invasive ductal BC were used in the study. DIA outputs were subsampled by HexT for ITH quantification and tumor microenvironment extraction for Immunogradient indicators. Multiple Cox regression revealed HER2 membrane completeness (HER2 MC) (HR: 0.18, p = 0.0007), its spatial entropy (HR: 0.37, p = 0.0341), and ER contrast (HR: 0.21, p = 0.0449) as independent predictors of better OS, with worse OS predicted by pT status (HR: 6.04, p = 0.0014) in the HER2 non-amplified patients. In the HER2-amplified patients, HER2 MC contrast (HR: 0.35, p = 0.0367) and CEP17 copy number (HR: 0.19, p = 0.0035) were independent predictors of better OS along with worse OS predicted by pN status (HR: 4.75, p = 0.0018). In the non-amplified tumors, three Immunogradient indicators provided the independent prognostic value: CD8 density in the tumor aspect of the IZ and CD8 center of mass were associated with better OS (HR: 0.23, p = 0.0079 and 0.14, p = 0.0014, respectively), and CD8 density variance along the tumor edge predicted worse OS (HR: 9.45, p = 0.0002). Combining these three computational indicators of the CD8 cell spatial distribution within the tumor microenvironment augmented prognostic stratification of the patients. In the HER2-amplified group, CD8 cell density in the tumor aspect of the IZ was the only independent immune response feature to predict better OS (HR: 0.22, p = 0.0047). In conclusion, we present novel prognostic models, based on computational ITH and Immunogradient indicators of the IHC biomarkers, in HER2 IHC 2+ BC patients. |
| format |
article |
| author |
Gedmante Radziuviene Gedmante Radziuviene Allan Rasmusson Allan Rasmusson Renaldas Augulis Renaldas Augulis Ruta Barbora Grineviciute Dovile Zilenaite Dovile Zilenaite Aida Laurinaviciene Aida Laurinaviciene Valerijus Ostapenko Arvydas Laurinavicius Arvydas Laurinavicius |
| author_facet |
Gedmante Radziuviene Gedmante Radziuviene Allan Rasmusson Allan Rasmusson Renaldas Augulis Renaldas Augulis Ruta Barbora Grineviciute Dovile Zilenaite Dovile Zilenaite Aida Laurinaviciene Aida Laurinaviciene Valerijus Ostapenko Arvydas Laurinavicius Arvydas Laurinavicius |
| author_sort |
Gedmante Radziuviene |
| title |
Intratumoral Heterogeneity and Immune Response Indicators to Predict Overall Survival in a Retrospective Study of HER2-Borderline (IHC 2+) Breast Cancer Patients |
| title_short |
Intratumoral Heterogeneity and Immune Response Indicators to Predict Overall Survival in a Retrospective Study of HER2-Borderline (IHC 2+) Breast Cancer Patients |
| title_full |
Intratumoral Heterogeneity and Immune Response Indicators to Predict Overall Survival in a Retrospective Study of HER2-Borderline (IHC 2+) Breast Cancer Patients |
| title_fullStr |
Intratumoral Heterogeneity and Immune Response Indicators to Predict Overall Survival in a Retrospective Study of HER2-Borderline (IHC 2+) Breast Cancer Patients |
| title_full_unstemmed |
Intratumoral Heterogeneity and Immune Response Indicators to Predict Overall Survival in a Retrospective Study of HER2-Borderline (IHC 2+) Breast Cancer Patients |
| title_sort |
intratumoral heterogeneity and immune response indicators to predict overall survival in a retrospective study of her2-borderline (ihc 2+) breast cancer patients |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/73d1a54944394a3f9f244347fdfc92a2 |
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