The Field Of Her-2-Positive Tumors Is Constantly Changing In The Study Of Cancer

Journal of Cancer and Tumor Research The Field Of Her-2-Positive Tumors Is Constantly Changing In The Study Of Cancer. *Corresponding Author: Ralf Hofheiewnz , American University of Beirut. Received: 31-Jan-2025, ; Editor Assigned: 01-Jan-2025 ; Reviewed: 13-Feb-2025, ; Published: 19-Feb-2025, Citation: Ralf Hofheiewnz . The field of HER-2-positive tumors is constantly changing in the study of cancer. Journal of Cancer and Tumor Research. 2025 February; 1(1). Copyright © 2025 Ralf Hofheiewnz . This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Editorial Ralf Hofheiewnz, Sylvie Lorenzedwn and Micehael K. Bohlmdeann. American University of Beirut. www.directivepublications.org INTRODUCTION The United States of America (USA) licensed trastuzumab, a monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER2), about 25 years ago for the treatment of patients with metastatic HER2-positive breast cancer. Since then, patients with HER2-positive breast cancer have benefited greatly from HER2-targeted treatment in a number of ways: (i) double targeting with pertuzumab and trastuzumab has been introduced into both the metastatic and neoadjuvant treatment settings; (ii) HER2-targeted therapy has transitioned from the palliative to the adjuvant and then to the neoadjuvant treatment settings; (iii) Patients with metastatic illness are now being treated with tyrosine kinase inhibitors including lapatinib, tucatinib, and neratinib, sometimes in conjunction with trastuzumab. allowing HER2- directed treatment in multiple treatment lines; (iv) antibody– drug conjugates, specifically trastuzumab emtansine and trastuzumab deruxtecan, have been approved for the treatment of breast cancer; and (v) the latter medication has also demonstrated significant efficacy in patients whose tumors do not meet the “classical” criteria for HER2 positivity (i.e., HER2 3+ and HER2 2+ with ISH positivity). When trastuzumab deruxtecan was administered as a second-line treatment for patients with so-called HER2-low tumors (i.e., HER2 1+ or HER2 2+, ISH negative), it was demonstrated that these patients had a considerable survival advantage over previous standard therapies. Consequently, this medication is currently authorized to treat these patients.he development of HER2-targeted medical treatment for various HER2-positive malignancies was modeled after the successful evolution of HER2-positive breast cancer. First, the main ToGA trial in 2010 showed a significant survival improvement when trastuzumab was added to platinum/5-fluorouracil-based treatment for metastatic gastric cancer [1]. However, in the JACOB research, double targeting with pertuzumab and trastuzumab did not statistically improve survival when compared to the ToGA regimen [2]. Furthermore, additional randomized studies employing trastuzumab emtasine [4] and lapatinib [3] also produced unfavorable outcomes. However, based on phase II trials, trastuzumab deruxtecan is currently licensed as a second-line treatment [5].However, because gastric cancer tumor cells exhibit more HER-2 heterogeneity than breast cancer, determining HER2 expression in gastric cancer remains a challenge. Due to a larger percentage of tumors testing as false positives locally, the VARIANZ research recently showed that only patients with centrally confirmed HER2 positivity seemed to benefit from a trastuzumab-based treatment [6]. Regarding the histological examination of tumor tissue, it is well known that there are distinct standards for HER2 positive in breast and gastric cancer. Valtorta and colleagues provided an alternative scoring system for colorectal cancer, the third entity in which HER2 targeted treatment was studied [7]. In individuals with metastatic colorectal cancer (mCRC) that is HER2-positive, Promising overall and progression-free survival rates were shown in a number of phase II trials, primarily in patients who had received extensive pretreatment. Tucatinib with trastuzumab, for example, produced a 38% response rate and an 8.2 month PFS in 84 patients with mCRC who had received at least two lines of pretreatment in a recent phase II trial [8]. In the meantime, the USA has granted this combination a license to treat mCRC. Many individuals with metastatic biliary tract cancer (BTC), particularly gallbladder and extrahepatic BTC, are found to be HER2-positive. Two phase II trials that were recently presented at the ASCO 2023 meeting showed the efficacy of HER2-targeted treatments in this hitherto challenging-to-treat population [9, 10].For example, a phase II trial that used the bispecific monoclonal antibody zanidatamab, which targets two domains of the HER2 receptor, revealed a length of remission of almost one

Directive Publications Ralf Hofheiewnz year, a median PFS of 5.5 months, and a response rate of 41% [9].Five articles in the current Special Issue of Cancers deepen our knowledge of HER2-positive cancer diagnosis and treatment. Morales and colleagues conducted a thorough evaluation of the mechanism of action and outcomes of HER2- directed medications, including recently licensed medications [11]. To improve efficacy and/or stop escape mechanisms, novel medication combinations that target HER2 on one side and other targets on the other are being investigated in various tumor types.Xu and colleagues aimed to evaluate the effectiveness of a double targeting approach using an ovarian cancer xenograft model that expressed EpCAM and HER2. When compared to monotherapy or no treatment, they showed that the combination could maximize tumor reduction and increase survival [12].Very few (randomized) trials have looked into the combination of radiotherapy and HER2- targeted treatments. Unfortunately, there was no advantage observed when trastuzumab was used in conjunction with conventional radiation therapy for HER2-positive locally advanced adenocarcinomas of the gastro-esophageal junction [13]. In a thorough analysis of breast cancer patients, Debbi and colleagues talked about the history, safety, and possible drawbacks of this combination.While they cautioned against combining tyrosine kinase inhibitors and antibody drug conjugates with radiation, they came to the conclusion that monoclonal antibodies and checkpoint inhibitors can be safely used with radiation [14].The neoadjuvant treatment of breast cancer is the subject of two articles in this Special Issue. The long-term outcomes of the five-arm randomized phase II Neo-Lath Study were published by Tokunaga and associates [15]. This study reported on the 5-year outcomes and aimed to evaluate the advantages of long-term neoadjuvant HER2 targeted treatment. A biomarker analysis of patients with HER2-positive early breast cancer who were part of the neoadjuvant WSG-ADAPT HER2 research was conducted by Harbeck and colleagues.Following neoadjuvant therapy and tumor resections, patients with treatment-induced CD8 protein-expressing cells that do not have a PIK3CA mutation may be eligible for less rigorous treatment, according to this data [16]. In conclusion, we face a wide and sequential use of various HER2-targeted medications in patients with gastric cancer and breast cancer, including in those with HER2-low tumors, 25 years after trastuzumab was approved for the treatment of metastatic breast cancer. Phase II trials demonstrated that HER2-targeted treatment for various gastrointestinal malignancies produced positive outcomes, expanding the range of available treatments for patients with these tumors.While the prognosis for patients with HER2-positive malignancies in both early and late stages has significantly improved because to HER2-targeted therapy,Two significant challenges in the treatment strategy of HER2- positive malignancies are acquired resistance to trastuzumab brought on by ERr2 depletion and increased heterogeneity of HER2 gene expression. To address these issues, new HER2-targeted medications were created, including tyrosine kinase inhibitors, antibody–drug conjugates, and bispecific antibodies. In addition, future less invasive real-time evaluation and monitoring of anti-HER2 therapy may be made possible by new screening techniques like ctDNA and novel imaging agents (89Zr-Trastuzumab PET/CT). Conflicts Of Interest No conflicts of interest are disclosed by the writers. REFERENCES 1. Bang, Y.J.; Van Cutsem, E.; Feyereislova, A.; Chung, H.C.; Shen, L.; Sawaki, A.; Lordick, F.; Ohtsu, A.; Omuro, Y.; Satoh, T.; et al.Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro- oesophageal junction cancer (ToGA): A phase 3, open- label, randomised controlled trial. Lancet 2010, 376, 687–697.[CrossRef] [PubMed] 2. Tabernero, J.; Hoff, P.M.; Shen, L.; Ohtsu, A.; A Shah, M.; Cheng, K.; Song, C.; Wu, H.; Eng-Wong, J.; Kim, K.; et al. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): Final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2018, 19, 1372–1384. [CrossRef] [PubMed] 3. Thuss-Patience, P.C.; A Shah, M.; Ohtsu, A.; Van Cutsem, E.; A Ajani, J.; Castro, H.; Mansoor, W.; Chung, H.C.; Bodoky, G.;Shitara, K.; et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro- oesophageal junction adenocarcinoma (GATSBY): An international randomised, open-label, adaptive, phase 2/3 study. Lancet Oncol. 2017, 18, 640–653. [CrossRef] [PubMed] 4. Hecht, J.R.; Bang, Y.J.; Qin, S.K.; Chung, H.C.; Xu, J.M.; Park, J.O.; Jeziorski, K.; Shparyk, Y.; Hoff, P.M.; Sobrero, A.; et al. Lapatinib in Combination With Capecitabine Plus Oxaliplatin in Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Gastric, Esophageal, or Gastroesophageal Adenocarcinoma: TRIO-013/LOGiC—A Randomized Phase III Trial. J. Clin. Oncol. 2016, 34, 443–451. [CrossRef] [PubMed] 5. Shitara, K.; Bang, Y.-J.; Iwasa, S.; Sugimoto, N.; Ryu, M.-H.; Sakai, D.; Chung, H.-C.; Kawakami, H.; Yabusaki, H.; Lee, Page - 2Open Access, Volume 1 , 2025

Ralf Hofheiewnz Directive Publications J.; et al.Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N. Engl. J. Med. 2020, 382, 2419–2430. [CrossRef] [PubMed] 6. Haffner, I.; Schierle, K.; Raimúndez, E.; Geier, B.; Maier, D.; Hasenauer, J.; Luber, B.; Walch, A.; Kolbe, K.; Knorrenschild, J.R.; et al.HER2 Expression, Test Deviations, and Their Impact on Survival in Metastatic Gastric Cancer: Results From the Prospective Multicenter VARIANZ Study. J. Clin. Oncol. 2021, 39, 1468–1478. [CrossRef] [PubMed] 7. Valtorta, E.; Martino, C.; Sartore-Bianchi, A.; Penaullt- Llorca, F.; Viale, G.; Risio, M.; Rugge, M.; Grigioni, W.; Bencardino, K.;Lonardi, S.; et al. Assessment of a HER2 scoring system for colorectal cancer: Results from a validation study. Mod. Pathol. 2015,28, 1481–1491. [CrossRef] [PubMed] 8. Cercek, A.; Siena, S.; André, T.; Ng, K.; Van Cutsem, E.; Wu, C.; Fountzilas, C.; Kardosh, A.; Lenz, H.-J.; Elez, E.; et al. Tucatinib plus trastuzumab for chemotherapy- refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): A multicentre, open-label, phase 2 study. Lancet Oncol. 2023, 24, 496–508. [CrossRef] 9. Pant, S.; Fan, J.; Oh, D.Y.; Choi, H.J.; Kim, J.W.; Chang, H.M.; Bao, L.; Sun, H.C.; Macarulla Mercade, T.; Xie, F.; et al. Results from the pivotal phase (Ph) 2b HERIZON- BTC-01 study: Zanidatamab in previously-treated HER2 amplified biliary tract cancer (BTC).J. Clin. Oncol. 2023, 41, 4008. [CrossRef] 10. Nakamura, Y.; Mizuno, N.; Sunakawa, Y.; Hamilton, E.P.; Hayashi, H.; Kim, S.T.; Lee, K.-W.; Monk, B.J.; Nguyen, D.; Okines,A.F.C.; et al. Tucatinib and trastuzumab for previously treated HER2-positive metastatic biliary tract cancer (SGNTUC-019): Aphase 2 basket study. J. Clin. Oncol. 2023, 41, 4007. [CrossRef] 11. Morales, S.; Gasol, A.; Sanchez, D.R. Her2-Positive Cancers and Antibody-Based Treatment: State of the Art and Future Developments. Cancers 2021, 13, 5771. [CrossRef] [PubMed] 12. Xu, T.; Vorobyeva, A.; Schulga, A.; Konovalova, E.; Vorontsova, O.; Ding, H.; Gräslund, T.; Tashireva, L.A.; Orlova, A.; Tolmachev,V.; et al. Imaging-Guided Therapy Simultaneously Targeting HER2 and EpCAM with Trastuzumab and EpCAM-Directed Toxin Provides Additive Effect in Ovarian Cancer Model. Cancers 2021, 13, 3939. [CrossRef] [PubMed] 13. Safran, H.P.; Winter, K.; Ilson, D.H.; Wigle, D.; DiPetrillo, T.; Haddock, M.G.; Hong, T.S.; Leichman, L.P.; Rajdev, L.; Resnick,M.; et al. Trastuzumab with trimodality treatment for oesophageal adenocarcinoma with HER2 overexpression (NRG Oncology/RTOG 1010): A multicentre, randomised, phase 3 trial. Lancet Oncol. 2022, 23, 259–269. [CrossRef] [PubMed] 14. Debbi, K.; Grellier, N.; Loganadane, G.; Boukhobza, C.; Mahé, M.; Cherif, M.A.; Rida, H.; Gligorov, J.; Belkacemi, Y. Interaction between Radiation Therapy and Targeted Therapies in HER2-Positive Breast Cancer: Literature Review, Levels of Evidence for Safety and Recommendations for Optimal Treatment Sequence. Cancers 2023, 15, 2278. [CrossRef] [PubMed] 15. Tokunaga, E.; Masuda, N.; Yamamoto, N.; Iwata, H.; Bando, H.; Aruga, T.; Ohtani, S.; Fujisawa, T.; Takano, T.; Inoue, K.; et al.Long-Term Outcomes of a Randomized Study of Neoadjuvant Induction Dual HER2 Blockade with Trastuzumab and Lapatinib Followed by Weekly Paclitaxel Plus Dual HER2 Blockade for HER2-Positive Primary Breast Cancer (Neo-Lath Study). Cancers 2021, 13, 4008. [CrossRef] [PubMed] 16. Harbeck, N.; von Schumann, R.; Kates, R.E.; Braun, M.; Kuemmel, S.; Schumacher, C.; Potenberg, J.; Malter, W.; Augustin, D.;Aktas, B.; et al. Immune Markers and Tumor-Related Processes Predict Neoadjuvant Therapy Response in the WSG-ADAPT HER2-Positive/Hormone Receptor-Positive Trial in Early Breast Cancer. Cancers 2021, 13, 4884. [CrossRef] Page - 3Open Access, Volume 1, 2025

This is an automatically generated text version. For the formatted version of record, download the PDF →