Appraisal of Systemic Treatment Strategies in Early HER2-Positive Breast Cancer—A Literature Review
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
3. HER2 as an Oncogenic Molecular Driver
4. Classification of HER2+ Tumors
5. Treatment Strategies for HER2+ Breast Cancer
5.1. Monoclonal Antibody against HER2
5.2. Dual HER2 Blockage with mABs
5.3. Antibody–Drug Conjugate
5.4. TKIs
6. Defining Risk Categories
7. Adjuvant Treatment
7.1. Very Low-Risk HER2+
7.2. Low-Risk HER2+
7.3. High-Risk HER2+
7.4. Adjuvant Dual HER2 Blockage
8. Neoadjuvant Treatment
9. Adjuvant HER2 Therapy in Postoperative Pathologic Residual Disease
10. Chemotherapy Backbone with versus without Anthracycline
11. Optimal HER2 Treatment Duration
12. Multigene Profiling Assays
13. Tumor-Infiltrating Lymphocytes
14. Immune Checkpoint Inhibitors
15. Future directions
15.1. Novel Targeted Therapies and Innovative Strategies
15.2. De-Escalation of Adjuvant Therapy
15.3. Other Oncodriver Mutations and Molecular Pathways Crossing with HER2+
PI3K/AKT/mTOR/MAPK Pathways
15.4. Cancer-Targeted Vaccines
16. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Mayer, E.L.; Fesl, C.; Hlauschek, D.; Garcia-Estevez, L.; Burstein, H.J.; Zdenkowski, N.; Wette, V.; Miller, K.D.; Balic, M.; Mayer, I.A.; et al. Treatment Exposure and Discontinuation in the PALbociclib CoLlaborative Adjuvant Study of Palbociclib with Adjuvant Endocrine Therapy for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer (PALLAS/AFT-05/ABCSG-42/BIG-14-03). J. Clin. Oncol. 2022, 40, 449–458. [Google Scholar] [CrossRef]
- Alferez, D.G.; Simões, B.M.; Howell, S.J.; Clarke, R.B. The Role of Steroid Hormones in Breast and Effects on Cancer Stem Cells. Curr. Stem Cell Rep. 2018, 4, 81–94. [Google Scholar] [CrossRef]
- Loibl, S.; Gianni, L. HER2-positive breast cancer. Lancet 2017, 389, 2415–2429. [Google Scholar] [CrossRef] [PubMed]
- Patel, A.; Unni, N.; Peng, Y. The Changing Paradigm for the Treatment of HER2-Positive Breast Cancer. Cancers 2020, 12, 2081. [Google Scholar] [CrossRef] [PubMed]
- Mata, D.G.D.M.M.; Carmona, A.; Eisen, C.; Trudeau, A.; Giffoni, D.; Morais Mata, M.; Carmona, C.A.; Eisen, A.; Trudeau, M. Appraising Adjuvant Endocrine Therapy in Hormone Receptor Positive HER2-Negative Breast Cancer—A Literature Review. Curr. Oncol. 2022, 29, 4956–4969. [Google Scholar] [CrossRef]
- Gradishar, W.J. HER2 Therapy—An Abundance of Riches. N. Engl. J. Med. 2012, 366, 176–178. [Google Scholar] [CrossRef] [PubMed]
- Lin, N.U.; Murthy, R.K.; Abramson, V.; Anders, C.; Bachelot, T.; Bedard, P.L.; Borges, V.; Cameron, D.; Carey, L.A.; Chien, A.J.; et al. Tucatinib vs. Placebo, Both in Combination with Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients with Brain Metastases: Updated Exploratory Analysis of the HER2CLIMB Randomized Clinical Trial. JAMA Oncol. 2023, 9, 197–205. [Google Scholar] [CrossRef]
- Swain, S.M.; Shastry, M.; Hamilton, E. Targeting HER2-positive breast cancer: Advances and future directions. Nat. Rev. Drug Discov. 2022, 22, 101–126. [Google Scholar] [CrossRef]
- Cortazar, P.; Zhang, L.; Untch, M.; Mehta, K.; Costantino, J.P.; Wolmark, N.; Bonnefoi, H.; Cameron, D.; Gianni, L.; Valagussa, P.; et al. Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet 2014, 384, 164–172. [Google Scholar] [CrossRef]
- Centre, P.C.; Perrin, J.; Gligorov, J.; Coudert, B.P.; Largillier, R.; Arnould, L.; Chollet, P.; Campone, M.; Coeffic, D.; Priou, F.; et al. Multicenter Phase II Trial of Neoadjuvant Therapy with Trastuzumab, Docetaxel, and Carboplatin for Human Epidermal Growth Factor Receptor-2-Overexpressing Stage II or III Breast Ca Spontaneous Canine Model View project Projects on ABC View project Multicenter Phase II Trial of Neoadjuvant Therapy with Trastuzumab, Docetaxel, and Carboplatin for Human Epidermal Growth Factor Receptor-2-Overexpressing Stage II or III Breast Cancer: Results of the GETN(A)-1 Trial. Artic. J. Clin. Oncol. 2007, 25, 2678–2684. [Google Scholar] [CrossRef]
- Coudert, B.P.; Arnould, L.; Moreau, L.; Chollet, P.; Weber, B.; Vanlemmens, L.; Moluçon, C.; Tubiana, N.; Causeret, S.; Misset, J.L.; et al. Pre-operative systemic (neo-adjuvant) therapy with trastuzumab and docetaxel for HER2-overexpressing stage II or III breast cancer: Results of a multicenter phase II trial. Ann. Oncol. 2006, 17, 409–414. [Google Scholar] [CrossRef] [PubMed]
- Buzdar, A.U.; Ibrahim, N.K.; Francis, D.; Booser, D.J.; Thomas, E.S.; Theriault, R.L.; Pusztai, L.; Green, M.C.; Arun, B.K.; Giordano, S.H.; et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: Results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J. Clin. Oncol. 2005, 23, 3676–3685. [Google Scholar] [CrossRef] [PubMed]
- Davey, M.G.; Browne, F.; Miller, N.; Lowery, A.J.; Kerin, M.J. Pathological complete response as a surrogate to improved survival in human epidermal growth factor receptor-2-positive breast cancer: Systematic review and meta-analysis. BJS Open 2022, 6, zrac028. [Google Scholar] [CrossRef] [PubMed]
- Shen, G.; Zhao, F.; Huo, X.; Ren, D.; Du, F.; Zheng, F.; Zhao, J. Meta-Analysis of HER2-Enriched Subtype Predicting the Pathological Complete Response within HER2-Positive Breast Cancer in Patients Who Received Neoadjuvant Treatment. Front. Oncol. 2021, 11, 632357. [Google Scholar] [CrossRef]
- Chumsri, S.; Li, Z.; Serie, D.J.; Mashadi-Hossein, A.; Colon-Otero, G.; Song, N.; Pogue-Geile, K.L.; Gavin, P.G.; Paik, S.; Moreno-Aspitia, A.; et al. Incidence of late relapses in patients with HER2-positive breast cancer receiving adjuvant trastuzumab: Combined analysis of NCCTG N9831 (Alliance) and NRG oncology/NSABP B-31. J. Clin. Oncol. 2019, 37, 3425–3435. [Google Scholar] [CrossRef]
- 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. Trastuzumab plus Adjuvant Chemotherapy for Operable HER2-Positive Breast Cancer. N. Engl. J. Med. 2005, 353, 1673–1684. [Google Scholar] [CrossRef]
- Cameron, D.; Piccart-Gebhart, M.J.; Gelber, R.D.; Procter, M.; Goldhirsch, A.; de Azambuja, E.; Castro, G.; Untch, M.; Smith, I.; Gianni, L.; et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: Final analysis of the HERceptin Adjuvant (HERA) trial. Lancet 2017, 389, 1195–1205. [Google Scholar] [CrossRef]
- Prat, A.; Guarneri, V.; Paré, L.; Griguolo, G.; Pascual, T.; Dieci, M.V.; Chic, N.; González-Farré, B.; Frassoldati, A.; Sanfeliu, E.; et al. A multivariable prognostic score to guide systemic therapy in early-stage HER2-positive breast cancer: A retrospective study with an external evaluation. Lancet Oncol. 2020, 21, 1455–1464. [Google Scholar] [CrossRef]
- Crosby, E.J.; Acharya, C.R.; Haddad, A.F.; Rabiola, C.A.; Lei, G.; Wei, J.P.; Yang, X.Y.; Wang, T.; Liu, C.X.; Wagner, K.U.; et al. Stimulation of oncogene-specific tumor-infiltrating T cells through combined vaccine and αPD1 enable sustained anti-tumor responses against established HER2 Breast Cancer. Clin. Cancer Res. 2020, 26, 4670–4681. [Google Scholar] [CrossRef]
- Lim, M.; Nguyen, T.H.; Niland, C.; Reid, L.E.; Jat, P.S.; Saunus, J.M.; Lakhani, S.R. Landscape of Epidermal Growth Factor Receptor Heterodimers in Brain Metastases. Cancers 2022, 14, 533. [Google Scholar] [CrossRef]
- Brockhoff, G. ‘Shedding’ light on HER4 signaling in normal and malignant breast tissues. Cell. Signal. 2022, 97, 110401. [Google Scholar] [CrossRef] [PubMed]
- Watanabe, S.; Yonesaka, K.; Tanizaki, J.; Nonagase, Y.; Takegawa, N.; Haratani, K.; Kawakami, H.; Hayashi, H.; Takeda, M.; Tsurutani, J.; et al. Targeting of the HER2/HER3 signaling axis overcomes ligand-mediated resistance to trastuzumab in HER2-positive breast cancer. Cancer Med. 2019, 8, 1258–1268. [Google Scholar] [CrossRef] [PubMed]
- Moasser, M.M. The oncogene HER2: Its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 2007, 26, 6469–6487. [Google Scholar] [CrossRef]
- Wolff, A.C.; Elizabeth Hale Hammond, M.; Allison, K.H.; Harvey, B.E.; Mangu, P.B.; Bartlett, J.M.S.; Bilous, M.; Ellis, I.O.; Fitzgibbons, P.; Hanna, W.; et al. Human epidermal growth factor receptor 2 testing in breast cancer: American society of clinical oncology/ college of American pathologists clinical practice guideline focused update. J. Clin. Oncol. 2018, 36, 2105–2122. [Google Scholar] [CrossRef]
- Jeyakumar, A.; Younis, T. Trastuzumab for HER2-Positive Metastatic Breast Cancer: Clinical and Economic Considerations. Clin. Med. Insights Oncol. 2012, 6, 179. [Google Scholar] [CrossRef] [PubMed]
- Wilson, F.R.; Coombes, M.E.; Wylie, Q.; Yurchenko, M.; Brezden-Masley, C.; Hutton, B.; Skidmore, B.; Cameron, C. Herceptin® (trastuzumab) in HER2-positive early breast cancer: Protocol for a systematic review and cumulative network meta-analysis. Syst. Rev. 2017, 6, 196. [Google Scholar] [CrossRef]
- Baselga, J. Treatment of HER2-overexpressing breast cancer. Ann. Oncol. 2010, 21 (Suppl. S7), vii36–vii40. [Google Scholar] [CrossRef] [PubMed]
- Bleesing, J.J.H.; Oliveira, J.B. Assessment of functional immune responses. In Clinical Immunology: Principles and Practice: Fourth Edition; Saunders: Philadelphia, PA, USA, 2013; pp. 1172–1182. [Google Scholar] [CrossRef]
- Perez, E.A.; Romond, E.H.; Suman, V.J.; Jeong, J.H.; Sledge, G.; Geyer, C.E.; Martino, S.; Rastogi, P.; Gralow, J.; Swain, S.M.; et al. Trastuzumab Plus Adjuvant Chemotherapy for Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Planned Joint Analysis of Overall Survival from NSABP B-31 and NCCTG N9831. J. Clin. Oncol. 2014, 32, 3744. [Google Scholar] [CrossRef] [PubMed]
- 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. [Google Scholar] [CrossRef]
- Siena, S.; Di Bartolomeo, M.; Raghav, K.; Masuishi, T.; Loupakis, F.; Kawakami, H.; Yamaguchi, K.; Nishina, T.; Fakih, M.; Elez, E.; et al. Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): A multicentre, open-label, phase 2 trial. Lancet Oncol. 2021, 22, 779–789. [Google Scholar] [CrossRef]
- Sukov, W.R.; Zhou, J.; Geiersbach, K.B.; Keeney, G.L.; Carter, J.M.; Schoolmeester, J.K. Frequency of HER2 protein overexpression and HER2 gene amplification in endometrial clear cell carcinoma. Hum. Pathol. 2023, 137, 94–110. [Google Scholar] [CrossRef]
- Cobleigh, M.A.; Vogel, C.L.; Tripathy, D.; Robert, N.J.; Scholl, S.; Fehrenbacher, L.; Wolter, J.M.; Paton, V.; Shak, S.; Lieberman, G.; et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J. Clin. Oncol. 1999, 17, 2639–2648. [Google Scholar] [CrossRef]
- Pegram, M.D.; Lipton, A.; Hayes, D.F.; Weber, B.L.; Baselga, J.M.; Tripathy, D.; Baly, D.; Baughman, S.A.; Twaddell, T.; Glaspy, J.A.; et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J. Clin. Oncol. 2016, 16, 2659–2671. [Google Scholar] [CrossRef] [PubMed]
- Slamon, D.; Eiermann, W.; Robert, N.; Pienkowski, T.; Martin, M.; Press, M.; Mackey, J.; Glaspy, J.; Chan, A.; Pawlicki, M.; et al. Adjuvant Trastuzumab in HER2-Positive Breast Cancer. N. Engl. J. Med. 2011, 365, 1273–1283. [Google Scholar] [CrossRef]
- Bradley, R.; Braybrooke, J.; Gray, R.; Hills, R.; Liu, Z.; Peto, R.; Davies, L.; Dodwell, D.; McGale, P.; Pan, H.; et al. Trastuzumab for early-stage, HER2-positive breast cancer: A meta-analysis of 13,864 women in seven randomised trials. Lancet Oncol. 2021, 22, 1139–1150. [Google Scholar] [CrossRef] [PubMed]
- Slamon, D.J.; Leyland-Jones, B.; Shak, S.; Fuchs, H.; Paton, V.; Bajamonde, A.; Fleming, T.; Eiermann, W.; Wolter, J.; Pegram, M.; et al. Use of Chemotherapy plus a Monoclonal Antibody against HER2 for Metastatic Breast Cancer That Overexpresses HER2. N. Engl. J. Med. 2001, 344, 783–792. [Google Scholar] [CrossRef] [PubMed]
- Lee-Hoeflich, S.T.; Crocker, L.; Yao, E.; Pham, T.; Munroe, X.; Hoeflich, K.P.; Sliwkowski, M.X.; Stern, H.M. A Central Role for HER3 in HER2-Amplified Breast Cancer: Implications for Targeted Therapy. Cancer Res. 2008, 68, 5878–5887. [Google Scholar] [CrossRef]
- Scheuer, W.; Friess, T.; Burtscher, H.; Bossenmaier, B.; Endl, J.; Hasmann, M. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 2009, 69, 9330–9336. [Google Scholar] [CrossRef]
- Verma, S.; Miles, D.; Gianni, L.; Krop, I.E.; Welslau, M.; Baselga, J.; Pegram, M.; Oh, D.-Y.; Diéras, V.; Guardino, E.; et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 2012, 367, 1783–1791. [Google Scholar] [CrossRef]
- FDA Approves Ado-Trastuzumab Emtansine for Early Breast Cancer|FDA. Available online: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ado-trastuzumab-emtansine-early-breast-cancer (accessed on 6 May 2023).
- Lewis Phillips, G.D.; Li, G.; Dugger, D.L.; Crocker, L.M.; Parsons, K.L.; Mai, E.; Blättler, W.A.; Lambert, J.M.; Chari, R.V.J.; Lutz, R.J.; et al. Targeting HER2-Positive Breast Cancer with Trastuzumab-DM1, an Antibody–Cytotoxic Drug Conjugate. Cancer Res. 2008, 68, 9280–9290. [Google Scholar] [CrossRef]
- Junttila, T.T.; Li, G.; Parsons, K.; Phillips, G.L.; Sliwkowski, M.X. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res. Treat. 2011, 128, 347–356. [Google Scholar] [CrossRef]
- Collins, D.M.; Conlon, N.T.; Kannan, S.; Verma, C.S.; Eli, L.D.; Lalani, A.S.; Crown, J. Preclinical Characteristics of the Irreversible Pan-HER Kinase Inhibitor Neratinib Compared with Lapatinib: Implications for the Treatment of HER2-Positive and HER2-Mutated Breast Cancer. Cancers 2019, 11, 737. [Google Scholar] [CrossRef] [PubMed]
- O’Shaughnessy, J.; Gradishar, W.; O’Regan, R.; Gadi, V. Risk of Recurrence in Patients with HER2+ Early-Stage Breast Cancer: Literature Analysis of Patient and Disease Characteristics. Clin. Breast Cancer 2023, 23, 350–362. [Google Scholar] [CrossRef]
- Yamashiro, H.; Iwata, H.; Masuda, N.; Yamamoto, N.; Nishimura, R.; Ohtani, S.; Sato, N.; Takahashi, M.; Kamio, T.; Yamazaki, K.; et al. Outcomes of trastuzumab therapy in HER2-positive early breast cancer patients: Extended follow-up of JBCRG-cohort study 01. Breast Cancer 2020, 27, 631–641. [Google Scholar] [CrossRef] [PubMed]
- Chou, H.H.; Chung, W.S.; Ding, R.Y.; Kuo, W.L.; Yu, C.C.; Tsai, H.P.; Shen, S.C.; Chu, C.H.; Lo, Y.F.; Chen, S.C. Factors affecting locoregional recurrence in breast cancer patients undergoing surgery following neoadjuvant treatment. BMC Surg. 2021, 21, 160. [Google Scholar] [CrossRef]
- O’Shaughnessy, J.; Robert, N.; Annavarapu, S.; Zhou, J.; Sussell, J.; Cheng, A.; Fung, A. Recurrence rates in patients with HER2+ breast cancer who achieved a pathological complete response after neoadjuvant pertuzumab plus trastuzumab followed by adjuvant trastuzumab: A real-world evidence study. Breast Cancer Res. Treat. 2021, 187, 903–913. [Google Scholar] [CrossRef]
- Moreno-Aspitia, A.; Holmes, E.M.; Jackisch, C.; de Azambuja, E.; Boyle, F.; Hillman, D.W.; Korde, L.; Fumagalli, D.; Izquierdo, M.A.; McCullough, A.E.; et al. Updated results from the international phase III ALTTO trial (BIG 2-06/Alliance N063D). Eur. J. Cancer 2021, 148, 287–296. [Google Scholar] [CrossRef] [PubMed]
- Lambertini, M.; Campbell, C.; Gelber, R.D.; Viale, G.; McCullough, A.; Hilbers, F.; Korde, L.A.; Werner, O.; Chumsri, S.; Jackisch, C.; et al. Dissecting the effect of hormone receptor status in patients with HER2-positive early breast cancer: Exploratory analysis from the ALTTO (BIG 2-06) randomized clinical trial. Breast Cancer Res. Treat. 2019, 177, 103–114. [Google Scholar] [CrossRef]
- Mamounas, E.P.; Untch, M.; Mano, M.S.; Huang, C.S.; Geyer, C.E.; von Minckwitz, G.; Wolmark, N.; Pivot, X.; Kuemmel, S.; DiGiovanna, M.P.; et al. Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: Subgroup analyses from KATHERINE. Ann. Oncol. 2021, 32, 1005–1014. [Google Scholar] [CrossRef]
- Korde, L.A.; Somerfield, M.R.; Carey, L.A.; Crews, J.R.; Denduluri, N.; Shelley Hwang, E.; Khan, S.A.; Loibl, S.; Morris, E.A.; Perez, A.; et al. Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline. J. Clin. Oncol. 2021, 39, 1485–1505. [Google Scholar] [CrossRef]
- Hortobagyi, G.N.; Edge, S.B.; Giuliano, A. New and Important Changes in the TNM Staging System for Breast Cancer. Am. Soc. Clin. Oncol. Educ. Book 2018, 38, 457–467. [Google Scholar] [CrossRef] [PubMed]
- Denduluri, N.; Somerfield, M.R.; Chavez-MacGregor, M.; Comander, A.H.; Dayao, Z.; Eisen, A.; Freedman, R.A.; Gopalakrishnan, R.; Graff, S.L.; Hassett, M.J.; et al. Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update. J. Clin. Oncol. 2021, 39, 685–693. [Google Scholar] [CrossRef]
- Gandhi, S.; Brackstone, M.; Hong, N.J.L.; Grenier, D.; Donovan, E.; Lu, F.I.; Skarpathiotakis, M.; Lee, J.; Boileau, J.F.; Perera, F.; et al. A Canadian national guideline on the neoadjuvant treatment of invasive breast cancer, including patient assessment, systemic therapy, and local management principles. Breast Cancer Res. Treat. 2022, 193, 1–20. [Google Scholar] [CrossRef] [PubMed]
- Gori, S.; Turazza, M.; Modena, A.; Duranti, S.; Zamboni, G.; Alongi, F.; Carbognin, G.; Massocco, A.; Salgarello, M.; Inno, A. When and how to treat women with HER2-positive, small (pT1a-b), node-negative breast cancer? Crit. Rev. Oncol./Hematol. 2018, 128, 130–138. [Google Scholar] [CrossRef]
- Vaz-Luis, I.; Ottesen, R.A.; Hughes, M.E.; Mamet, R.; Burstein, H.J.; Edge, S.B.; Gonzalez-Angulo, A.M.; Moy, B.; Rugo, H.S.; Theriault, R.L.; et al. Outcomes by tumor subtype and treatment pattern in women with small, node-negative breast cancer: A multi-institutional study. J. Clin. Oncol. 2014, 32, 2142–2150. [Google Scholar] [CrossRef]
- Hassing, C.M.S.; Nielsen, D.L.; Knoop, A.S.; Tvedskov, T.H.F.; Kroman, N.; Lænkholm, A.V.; Juhl, C.B.; Kümler, I. Adjuvant treatment with trastuzumab of patients with HER2-positive, T1a-bN0M0 breast tumors: A systematic review and meta-analysis. Crit. Rev. Oncol./Hematol. 2023, 184, 103952. [Google Scholar] [CrossRef] [PubMed]
- Fehrenbacher, L.; Capra, A.M.; Quesenberry, C.P.; Fulton, R.; Shiraz, P.; Habel, L.A. Distant invasive breast cancer recurrence risk in human epidermal growth factor receptor 2-positive T1a and T1b node-negative localized breast cancer diagnosed from 2000 to 2006: A cohort from an integrated health care delivery system. J. Clin. Oncol. 2014, 32, 2151–2158. [Google Scholar] [CrossRef]
- O’Sullivan, C.C.; Bradbury, I.; Campbell, C.; Spielmann, M.; Perez, E.A.; Joensuu, H.; Costantino, J.P.; Delaloge, S.; Rastogi, P.; Zardavas, D.; et al. Efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2-positive early breast cancer and tumors ≤ 2 cm: A meta-analysis of the randomized trastuzumab trials. J. Clin. Oncol. 2015, 33, 2600–2608. [Google Scholar] [CrossRef]
- Tolaney, S.M.; Barry, W.T.; Dang, C.T.; Yardley, D.A.; Moy, B.; Marcom, P.K.; Albain, K.S.; Rugo, H.S.; Ellis, M.; Shapira, I.; et al. Adjuvant Paclitaxel and Trastuzumab for Node-Negative, HER2-Positive Breast Cancer. N. Engl. J. Med. 2015, 372, 134–141. [Google Scholar] [CrossRef]
- Tolaney, S.M.; Guo, H.; Pernas, S.; Barry, W.T.; Dillon, D.A.; Ritterhouse, L.; Schneider, B.P.; Shen, F.; Fuhrman, K.; Baltay, M.; et al. Seven-year follow-up analysis of adjuvant paclitaxel and trastuzumab trial for node-negative, human epidermal growth factor receptor 2–positive breast cancer. J. Clin. Oncol. 2019, 37, 1868–1875. [Google Scholar] [CrossRef]
- Tolaney, S.M.; Tarantino, P.; Graham, N.; Tayob, N.; Parè, L.; Villacampa, G.; Dang, C.T.; Yardley, D.A.; Moy, B.; Marcom, P.K.; et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer: Final 10-year analysis of the open-label, single-arm, phase 2 APT trial. Lancet Oncol. 2023, 24, 273–285. [Google Scholar] [CrossRef]
- Tolaney, S.M.; Tayob, N.; Dang, C.; Yardley, D.A.; Isakoff, S.J.; Valero, V.; Faggen, M.; Mulvey, T.; Bose, R.; Hu, J.; et al. Adjuvant Trastuzumab Emtansine versus Paclitaxel in Combination with Trastuzumab for Stage I HER2-Positive Breast Cancer (ATEMPT): A Randomized Clinical Trial. J. Clin. Oncol. 2021, 39, 2375–2385. [Google Scholar] [CrossRef]
- Sella, T.; Zheng, Y.; Tayob, N.; Ruddy, K.J.; Freedman, R.A.; Dang, C.; Yardley, D.; Isakoff, S.J.; Valero, V.; DeMeo, M.; et al. Treatment discontinuation, patient-reported toxicities and quality-of-life by age following trastuzumab emtansine or paclitaxel/trastuzumab (ATEMPT). NPJ Breast Cancer 2022, 8, 127. [Google Scholar] [CrossRef] [PubMed]
- Swain, S.M.; Miles, D.; Kim, S.B.; Im, Y.H.; Im, S.A.; Semiglazov, V.; Ciruelos, E.; Schneeweiss, A.; Loi, S.; Monturus, E.; et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): End-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020, 21, 519–530. [Google Scholar] [CrossRef] [PubMed]
- von Minckwitz, G.; Procter, M.; de Azambuja, E.; Zardavas, D.; Benyunes, M.; Viale, G.; Suter, T.; Arahmani, A.; Rouchet, N.; Clark, E.; et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. N. Engl. J. Med. 2017, 377, 122–131. [Google Scholar] [CrossRef] [PubMed]
- Loibl, S.; Jassem, J.; Sonnenblick, A.; Parlier, D.; Winer, E.; Bergh, J.; Gelber, R.D.; Restuccia, E.; Im, Y.-H.; Huang, C.; et al. VP6-2022: Adjuvant pertuzumab and trastuzumab in patients with early HER-2 positive breast cancer in APHINITY: 8.4 years’ follow-up. Ann. Oncol. 2022, 33, 986–987. [Google Scholar] [CrossRef]
- Krop, I.E.; Im, S.A.; Barrios, C.; Bonnefoi, H.; Gralow, J.; Toi, M.; Ellis, P.A.; Gianni, L.; Swain, S.M.; Im, Y.H.; et al. Trastuzumab Emtansine Plus Pertuzumab Versus Taxane Plus Trastuzumab Plus Pertuzumab After Anthracycline for High-Risk Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: The Phase III KAITLIN Study. J. Clin. Oncol. 2022, 40, 438–448. [Google Scholar] [CrossRef]
- Gianni, L.; Eiermann, W.; Semiglazov, V.; Lluch, A.; Tjulandin, S.; Zambetti, M.; Moliterni, A.; Vazquez, F.; Byakhov, M.J.; Lichinitser, M.; et al. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): Follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol. 2014, 15, 640–647. [Google Scholar] [CrossRef]
- Gianni, L.; Pienkowski, T.; Im, Y.H.; Roman, L.; Tseng, L.M.; Liu, M.C.; Lluch, A.; Staroslawska, E.; de la Haba-Rodriguez, J.; Im, S.A.; et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012, 13, 25–32. [Google Scholar] [CrossRef]
- Gianni, L.; Pienkowski, T.; Im, Y.H.; Tseng, L.M.; Liu, M.C.; Lluch, A.; Starosławska, E.; de la Haba-Rodriguez, J.; Im, S.A.; Pedrini, J.L.; et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): A multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016, 17, 791–800. [Google Scholar] [CrossRef]
- Chen, S.; Liang, Y.; Feng, Z.; Wang, M. Efficacy and safety of HER2 inhibitors in combination with or without pertuzumab for HER2-positive breast cancer: A systematic review and meta-analysis. BMC Cancer 2019, 19, 973. [Google Scholar] [CrossRef] [PubMed]
- Hurvitz, S.A.; Martin, M.; Symmans, W.F.; Jung, K.H.; Huang, C.S.; Thompson, A.M.; Harbeck, N.; Valero, V.; Stroyakovskiy, D.; Wildiers, H.; et al. Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): A randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2018, 19, 115–126. [Google Scholar] [CrossRef] [PubMed]
- Hurvitz, S.A.; Martin, M.; Jung, K.H.; Huang, C.S.; Harbeck, N.; Valero, V.; Stroyakovskiy, D.; Wildiers, H.; Campone, M.; Boileau, J.F.; et al. Neoadjuvant Trastuzumab Emtansine and Pertuzumab in Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Three-Year Outcomes from the Phase III KRISTINE Study. J. Clin. Oncol. 2019, 37, 2206–2216. [Google Scholar] [CrossRef]
- Guarneri, V.; Griguolo, G.; Miglietta, F.; Conte, P.F.; Dieci, M.V.; Girardi, F. Survival after neoadjuvant therapy with trastuzumab–lapatinib and chemotherapy in patients with HER2-positive early breast cancer: A meta-analysis of randomized trials. ESMO Open 2022, 7, 100433. [Google Scholar] [CrossRef]
- Carey, L.A.; Berry, D.A.; Cirrincione, C.T.; Barry, W.T.; Pitcher, B.N.; Harris, L.N.; Ollila, D.W.; Krop, I.E.; Henry, N.L.; Weckstein, D.J.; et al. Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab with or Without Lapatinib. J. Clin. Oncol. 2016, 34, 542. [Google Scholar] [CrossRef] [PubMed]
- Huober, J.; Holmes, E.; Baselga, J.; de Azambuja, E.; Untch, M.; Fumagalli, D.; Sarp, S.; Lang, I.; Smith, I.; Boyle, F.; et al. Survival outcomes of the NeoALTTO study (BIG 1-06): Updated results of a randomised multicenter phase III neoadjuvant clinical trial in patients with HER2-positive primary breast cancer. Eur. J. Cancer 2019, 118, 169–177. [Google Scholar] [CrossRef] [PubMed]
- Rastogi, P.; Tang, G.; Hassan, S.; Geyer, C.E.; Azar, C.A.; Magrinat, G.C.; Suga, J.M.; Bear, H.D.; Baez-Diaz, L.; Sarwar, S.; et al. Long-term outcomes of dual vs. single HER2-directed neoadjuvant therapy in NSABP B-41. Breast Cancer Res. Treat. 2023, 199, 243–252. [Google Scholar] [CrossRef]
- von Minckwitz, G.; Huang, C.-S.; Mano, M.S.; Loibl, S.; Mamounas, E.P.; Untch, M.; Wolmark, N.; Rastogi, P.; Schneeweiss, A.; Redondo, A.; et al. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. N. Engl. J. Med. 2019, 380, 617–628. [Google Scholar] [CrossRef]
- Chan, A.; Delaloge, S.; Holmes, F.A.; Moy, B.; Iwata, H.; Harvey, V.J.; Robert, N.J.; Silovski, T.; Gokmen, E.; von Minckwitz, G.; et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016, 17, 367–377. [Google Scholar] [CrossRef]
- Martin, M.; Holmes, F.A.; Ejlertsen, B.; Delaloge, S.; Moy, B.; Iwata, H.; von Minckwitz, G.; Chia, S.K.L.; Mansi, J.; Barrios, C.H.; et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017, 18, 1688–1700. [Google Scholar] [CrossRef]
- Chan, A.; Moy, B.; Mansi, J.; Ejlertsen, B.; Holmes, F.A.; Chia, S.; Iwata, H.; Gnant, M.; Loibl, S.; Barrios, C.H.; et al. Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer from the Phase III ExteNET Trial. Clin. Breast Cancer 2021, 21, 80–91.e7. [Google Scholar] [CrossRef]
- Holmes, F.A.; Moy, B.; Delaloge, S.; Chia, S.K.L.; Ejlertsen, B.; Mansi, J.; Iwata, H.; Gnant, M.; Buyse, M.; Barrios, C.H.; et al. Overall survival with neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): A randomised, double-blind, placebo-controlled, phase 3 trial. Eur. J. Cancer 2023, 184, 48–59. [Google Scholar] [CrossRef] [PubMed]
- van Ramshorst, M.S.; van der Voort, A.; van Werkhoven, E.D.; Mandjes, I.A.; Kemper, I.; Dezentjé, V.O.; Oving, I.M.; Honkoop, A.H.; Tick, L.W.; van de Wouw, A.J.; et al. Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): A multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018, 19, 1630–1640. [Google Scholar] [CrossRef] [PubMed]
- van der Voort, A.; van Ramshorst, M.S.; van Werkhoven, E.D.; Mandjes, I.A.; Kemper, I.; Vulink, A.J.; Oving, I.M.; Honkoop, A.H.; Tick, L.W.; van de Wouw, A.J.; et al. Three-Year Follow-up of Neoadjuvant Chemotherapy with or without Anthracyclines in the Presence of Dual ERBB2 Blockade in Patients with ERBB2-Positive Breast Cancer: A Secondary Analysis of the TRAIN-2 Randomized, Phase 3 Trial. JAMA Oncol. 2021, 7, 978–984. [Google Scholar] [CrossRef] [PubMed]
- Slamon, D.; Eiermann, W.; Robert, N.; Giermek, J.; Martin, M.; Jasiowka, M.; Mackey, J.; Chan, A.; Liu, M.-C.; Pinter, T.; et al. Abstract S5-04: Ten year follow-up of BCIRG-006 comparing doxorubicin plus cyclophosphamide followed by docetaxel (AC→T) with doxorubicin plus cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in HER2+ early breast cancer. Cancer Res. 2016, 76 (Suppl. S4), S5-04. [Google Scholar] [CrossRef]
- Zhu, J.; Min, N.; Chen, Y.; Li, X. Neoadjuvant therapy with vs. without anthracyclines for HER2-positive breast cancer: A systematic review and meta-analysis. Ann. Transl. Med. 2023, 11, 200. [Google Scholar] [CrossRef]
- Schneeweiss, A.; Chia, S.; Hickish, T.; Harvey, V.; Eniu, A.; Hegg, R.; Tausch, C.; Seo, J.H.; Tsai, Y.F.; Ratnayake, J.; et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA). Ann. Oncol. 2013, 24, 2278–2284. [Google Scholar] [CrossRef]
- Schneeweiss, A.; Chia, S.; Hickish, T.; Harvey, V.; Eniu, A.; Waldron-Lynch, M.; Eng-Wong, J.; Kirk, S.; Cortés, J. Long-term efficacy analysis of the randomised, phase II TRYPHAENA cardiac safety study: Evaluating pertuzumab and trastuzumab plus standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer. Eur. J. Cancer 2018, 89, 27–35. [Google Scholar] [CrossRef]
- Goldhirsch, A.; Gelber, R.D.; Piccart-Gebhart, M.J.; De Azambuja, E.; Procter, M.; Suter, T.M.; Jackisch, C.; Cameron, D.; Weber, H.A.; Heinzmann, D.; et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): An open-label, randomised controlled trial. Lancet 2013, 382, 1021–1028. [Google Scholar] [CrossRef]
- Pondé, N.; Gelber, R.D.; Piccart, M. PERSEPHONE: Are we ready to de-escalate adjuvant trastuzumab for HER2-positive breast cancer? Npj Breast Cancer 2019, 5, 1. [Google Scholar] [CrossRef]
- Earl, H.M.; Hiller, L.; Vallier, A.L.; Loi, S.; McAdam, K.; Hughes-Davies, L.; Harnett, A.N.; Ah-See, M.L.; Simcock, R.; Rea, D.; et al. 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial. Lancet 2019, 393, 2599. [Google Scholar] [CrossRef] [PubMed]
- Pivot, X.; Romieu, G.; Debled, M.; Pierga, J.Y.; Kerbrat, P.; Bachelot, T.; Lortholary, A.; Espié, M.; Fumoleau, P.; Serin, D.; et al. 6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): Final analysis of a multicentre, open-label, phase 3 randomised trial. Lancet 2019, 393, 2591–2598. [Google Scholar] [CrossRef] [PubMed]
- Mavroudis, D.; Saloustros, E.; Malamos, N.; Kakolyris, S.; Boukovinas, I.; Papakotoulas, P.; Kentepozidis, N.; Ziras, N.; Georgoulias, V. Six versus 12 months of adjuvant trastuzumab in combination with dose-dense chemotherapy for women with HER2-positive breast cancer: A multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann. Oncol. 2015, 26, 1333–1340. [Google Scholar] [CrossRef] [PubMed]
- Chen, L.; Zhou, W.; Hu, X.; Yi, M.; Ye, C.; Yao, G. Short-duration versus 1-year adjuvant trastuzumab in early HER2 positive breast cancer: A meta-analysis of randomized controlled trials. Cancer Treat. Rev. 2019, 75, 12–19. [Google Scholar] [CrossRef] [PubMed]
- Pivot, X.; Romieu, G.; Debled, M.; Pierga, J.Y.; Kerbrat, P.; Bachelot, T.; Lortholary, A.; Espié, M.; Fumoleau, P.; Serin, D.; et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): A randomised phase 3 trial. Lancet Oncol. 2013, 14, 741–748. [Google Scholar] [CrossRef] [PubMed]
- Stewart, P.; Blanchette, P.; Shah, P.S.; Ye, X.Y.; Boldt, R.G.; Fernandes, R.; Vandenberg, T.; Raphael, J. Do all patients with HER2 positive breast cancer require one year of adjuvant trastuzumab? A systematic review and meta-analysis. Breast 2020, 54, 203–210. [Google Scholar] [CrossRef]
- Buus, R.; Sestak, I.; Kronenwett, R.; Ferree, S.; Schnabel, C.A.; Baehner, F.L.; Mallon, E.A.; Cuzick, J.; Dowsett, M. Molecular Drivers of Oncotype DX, Prosigna, EndoPredict, and the Breast Cancer Index: A TransATAC Study. J. Clin. Oncol. 2021, 39, 126. [Google Scholar] [CrossRef] [PubMed]
- Andre, F.; Ismaila, N.; Allison, K.H.; Barlow, W.E.; Collyar, D.E.; Damodaran, S.; Henry, N.L.; Jhaveri, K.; Kalinsky, K.; Kuderer, N.M.; et al. Biomarkers for Adjuvant Endocrine and Chemotherapy in Early-Stage Breast Cancer: ASCO Guideline Update. J. Clin. Oncol. 2022, 40, 1816–1837. [Google Scholar] [CrossRef]
- Griguolo, G.; Bottosso, M.; Vernaci, G.; Miglietta, F.; Dieci, M.V.; Guarneri, V. Gene-expression signatures to inform neoadjuvant treatment decision in HR+/HER2− breast cancer: Available evidence and clinical implications. Cancer Treat. Rev. 2022, 102, 102323. [Google Scholar] [CrossRef] [PubMed]
- Burstein, H.J.; Curigliano, G.; Thürlimann, B.; Weber, W.P.; Poortmans, P.; Regan, M.M.; Senn, H.J.; Winer, E.P.; Gnant, M.; Aebi, S.; et al. Customizing local and systemic therapies for women with early breast cancer: The St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. Ann. Oncol. 2021, 32, 1216–1235. [Google Scholar] [CrossRef]
- Waks, A.G.; Ogayo, E.R.; Paré, L.; Marín-Aguilera, M.; Brasó-Maristany, F.; Galván, P.; Castillo, O.; Martínez-Sáez, O.; Vivancos, A.; Villagrasa, P.; et al. Assessment of the HER2DX Assay in Patients with ERBB2-Positive Breast Cancer Treated With Neoadjuvant Paclitaxel, Trastuzumab, and Pertuzumab. JAMA Oncol. 2023, 9, 835–840. [Google Scholar] [CrossRef] [PubMed]
- Prat, A.; Guarneri, V.; Pascual, T.; Brasó-Maristany, F.; Sanfeliu, E.; Paré, L.; Schettini, F.; Martínez, D.; Jares, P.; Griguolo, G.; et al. Development and validation of the new HER2DX assay for predicting pathological response and survival outcome in early-stage HER2-positive breast cancer. EBioMedicine 2022, 75, 103801. [Google Scholar] [CrossRef]
- Luckheeram, R.V.; Zhou, R.; Verma, A.D.; Xia, B. CD4+T Cells: Differentiation and Functions. Clin. Dev. Immunol. 2012, 2012, 925135. [Google Scholar] [CrossRef] [PubMed]
- Jewett, A.; Tseng, H.C. Immunotherapy. In Pharmacology and Therapeutics for Dentistry, 7th ed.; Mosby: St. Louis, MO, USA, 2017; pp. 504–529. [Google Scholar] [CrossRef]
- Hwang, H.W.; Hong, S.A.; Nam, S.J.; Kim, S.W.; Lee, J.E.; Yu, J.H.; Lee, S.K.; Cho, S.Y.; Cho, E.Y. Histologic analysis according to HER2 gene status in HER2 2 + invasive breast cancer: A study of 280 cases comparing ASCO/CAP 2013 and 2018 guideline recommendations. Virchows Arch. 2022, 480, 749–758. [Google Scholar] [CrossRef]
- Paijens, S.T.; Vledder, A.; de Bruyn, M.; Nijman, H.W. Tumor-infiltrating lymphocytes in the immunotherapy era. Cell. Mol. Immunol. 2021, 18, 842–859. [Google Scholar] [CrossRef]
- Savas, P.; Virassamy, B.; Ye, C.; Salim, A.; Mintoff, C.P.; Caramia, F.; Salgado, R.; Byrne, D.J.; Teo, Z.L.; Dushyanthen, S.; et al. Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat. Med. 2018, 24, 986–993. [Google Scholar] [CrossRef] [PubMed]
- Loi, S.; Michiels, S.; Adams, S.; Loibl, S.; Budczies, J.; Denkert, C.; Salgado, R. The journey of tumor-infiltrating lymphocytes as a biomarker in breast cancer: Clinical utility in an era of checkpoint inhibition. Ann. Oncol. 2021, 32, 1236–1244. [Google Scholar] [CrossRef] [PubMed]
- Fernandez-Martinez, A.; Pascual, T.; Singh, B.; Nuciforo, P.; Rashid, N.U.; Ballman, K.V.; Campbell, J.D.; Hoadley, K.A.; Spears, P.A.; Pare, L.; et al. Prognostic and Predictive Value of Immune-Related Gene Expression Signatures vs. Tumor-Infiltrating Lymphocytes in Early-Stage ERBB2/HER2-Positive Breast Cancer: A Correlative Analysis of the CALGB 40601 and PAMELA Trials. JAMA Oncol. 2023, 9, 490–499. [Google Scholar] [CrossRef]
- Li, S.; Zhang, Y.; Zhang, P.; Xue, S.; Chen, Y.; Sun, L.; Yang, R. Predictive and prognostic values of tumor infiltrating lymphocytes in breast cancers treated with neoadjuvant chemotherapy: A meta-analysis. Breast 2022, 66, 97–109. [Google Scholar] [CrossRef]
- Salgado, R.; Denkert, C.; Campbell, C.; Savas, P.; Nuciforo, P.; Aura, C.; De Azambuja, E.; Eidtmann, H.; Ellis, C.E.; Baselga, J.; et al. Tumor-Infiltrating Lymphocytes and Associations With Pathological Complete Response and Event-Free Survival in HER2-Positive Early-Stage Breast Cancer Treated with Lapatinib and Trastuzumab: A Secondary Analysis of the NeoALTTO Trial. JAMA Oncol. 2015, 1, 448–455. [Google Scholar] [CrossRef]
- Gonzalez-Ericsson, P.I.; Stovgaard, E.S.; Sua, L.F.; Reisenbichler, E.; Kos, Z.; Carter, J.M.; Michiels, S.; Le Quesne, J.; Nielsen, T.O.; Lænkholm, A.V.; et al. The path to a better biomarker: Application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers in breast cancer clinical trials and daily practice. J. Pathol. 2020, 250, 667–684. [Google Scholar] [CrossRef]
- Rimawi, M.F.; Schiff, R.; Osborne, C.K. Targeting HER2 for the Treatment of Breast Cancer. Annu. Rev. Med. 2015, 66, 111–128. [Google Scholar] [CrossRef] [PubMed]
- Krasniqi, E.; Barchiesi, G.; Pizzuti, L.; Mazzotta, M.; Venuti, A.; Maugeri-Saccà, M.; Sanguineti, G.; Massimiani, G.; Sergi, D.; Carpano, S.; et al. Immunotherapy in HER2-positive breast cancer: State of the art and future perspectives. J. Hematol. Oncol. 2019, 12, 111. [Google Scholar] [CrossRef]
- Kyriazoglou, A.; Kaparelou, M.; Goumas, G.; Liontos, M.; Zakopoulou, R.; Zografos, E.; Zygogianni, A.; Dimopoulos, M.A.; Zagouri, F. Immunotherapy in HER2-Positive Breast Cancer: A Systematic Review. Breast Care 2022, 17, 63. [Google Scholar] [CrossRef] [PubMed]
- Loi, S.; Giobbie-Hurder, A.; Gombos, A.; Bachelot, T.; Hui, R.; Curigliano, G.; Campone, M.; Biganzoli, L.; Bonnefoi, H.; Jerusalem, G.; et al. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): A single-arm, multicentre, phase 1b-2 trial. Lancet Oncol. 2019, 20, 371–382. [Google Scholar] [CrossRef] [PubMed]
- Emens, L.A.; Esteva, F.J.; Beresford, M.; Saura, C.; De Laurentiis, M.; Kim, S.B.; Im, S.A.; Wang, Y.; Salgado, R.; Mani, A.; et al. Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): A phase 2, multicentre, randomised, double-blind trial. Lancet Oncol. 2020, 21, 1283–1295. [Google Scholar] [CrossRef]
- Huober, J.; Barrios, C.H.; Niikura, N.; Jarząb, M.; Chang, Y.C.; Huggins-Puhalla, S.L.; Pedrini, J.; Zhukova, L.; Graupner, V.; Eiger, D.; et al. Atezolizumab with Neoadjuvant Anti-Human Epidermal Growth Factor Receptor 2 Therapy and Chemotherapy in Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer: Primary Results of the Randomized Phase III IMpassion050 Trial. J. Clin. Oncol. 2022, 40, 2946–2956. [Google Scholar] [CrossRef]
- Schmid, P.; Cortes, J.; Dent, R.; Pusztai, L.; McArthur, H.; Kümmel, S.; Bergh, J.; Denkert, C.; Park, Y.H.; Hui, R.; et al. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. N. Engl. J. Med. 2022, 386, 556–567. [Google Scholar] [CrossRef]
- Schmid, P.; Cortes, J.; Pusztai, L.; McArthur, H.; Kümmel, S.; Bergh, J.; Denkert, C.; Park, Y.H.; Hui, R.; Harbeck, N.; et al. Pembrolizumab for Early Triple-Negative Breast Cancer. N. Engl. J. Med. 2020, 382, 810–821. [Google Scholar] [CrossRef]
- Hurvitz, S.A.; Bachelot, T.; Bianchini, G.; Harbeck, N.; Loi, S.; Park, Y.H.; Prat, A.; Gilham, L.; Boulet, T.; Monturus, N.G.E.; et al. ASTEFANIA: Adjuvant ado-trastuzumab emtansine and atezolizumab for high-risk, HER2-positive breast cancer. Future Oncol. 2022, 18, 3563–3572. [Google Scholar] [CrossRef]
- Neoadjuvant Treatment of HER2 Positive Early High-Risk and Locally Advanced Breast Cancer. ClinicalTrials.gov. (n.d.). Available online: https://clinicaltrials.gov/ct2/show/NCT03595592 (accessed on 1 June 2023).
- Neoadjuvant Her2-targeted Therapy and Immunotherapy with Pembrolizumab. ClinicalTrials.gov. (n.d.). Available online: https://clinicaltrials.gov/ct2/show/NCT03747120?term=HER2-POSITIVE+ADJUVANT+PEMBROLIZUMAB&cond=BREAST+CANCER&draw=2&rank=1 (accessed on 1 June 2023).
- Modi, S.; Jacot, W.; Yamashita, T.; Sohn, J.; Vidal, M.; Tokunaga, E.; Tsurutani, J.; Ueno, N.T.; Prat, A.; Chae, Y.S.; et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N. Engl. J. Med. 2022, 387, 9–20. [Google Scholar] [CrossRef]
- Hurvitz, S.A.; Hegg, R.; Chung, W.P.; Im, S.A.; Jacot, W.; Ganju, V.; Chiu, J.W.Y.; Xu, B.; Hamilton, E.; Madhusudan, S.; et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: Updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet 2023, 401, 105–117. [Google Scholar] [CrossRef] [PubMed]
- A Study of Trastuzumab Deruxtecan (T-DXd) versus Trastuzumab Emtansine (T-DM1) in High-Risk HER2-Positive Participants with Residual Invasive Breast Cancer Following Neoadjuvant Therapy (DESTINY-Breast05). ClinicalTrials.gov. (n.d.). Available online: https://clinicaltrials.gov/ct2/show/NCT04622319?cond=DESTINY-Breast05&draw=2&rank=1 (accessed on 5 May 2023).
- Trastuzumab Deruxtecan (T-DXd) Alone or in Sequence with THP, versus Standard Treatment (ddAC-THP), in HER2-Positive Early Breast Cancer. ClinicalTrials.gov. (n.d.). Available online: https://clinicaltrials.gov/ct2/show/NCT05113251?term=DESTINY+11&draw=2&rank=1 (accessed on 25 May 2023).
- Borges, V.F.; Ferrario, C.; Aucoin, N.; Falkson, C.; Khan, Q.; Krop, I.; Welch, S.; Conlin, A.; Chaves, J.; Bedard, P.L.; et al. Tucatinib Combined with Ado-Trastuzumab Emtansine in Advanced ERBB2/HER2-Positive Metastatic Breast Cancer: A Phase 1b Clinical Trial. JAMA Oncol. 2018, 4, 1214–1220. [Google Scholar] [CrossRef]
- Moulder, S.L.; Borges, V.F.; Baetz, T.; Mcspadden, T.; Fernetich, G.; Murthy, R.K.; Chavira, R.; Guthrie, K.; Barrett, E.; Chia, S.K. Phase I Study of ONT-380, a HER2 Inhibitor, in Patients with HER2+-Advanced Solid Tumors, with an Expansion Cohort in HER2+ Metastatic Breast Cancer (MBC). Clin. Cancer Res. 2017, 23, 3529–3536. [Google Scholar] [CrossRef] [PubMed]
- Murthy, R.K.; Loi, S.; Okines, A.; Paplomata, E.; Hamilton, E.; Hurvitz, S.A.; Lin, N.U.; Borges, V.; Abramson, V.; Anders, C.; et al. Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer. N. Engl. J. Med. 2020, 382, 597–609. [Google Scholar] [CrossRef] [PubMed]
- Curigliano, G.; Mueller, V.; Borges, V.; Hamilton, E.; Hurvitz, S.; Loi, S.; Murthy, R.; Okines, A.; Paplomata, E.; Cameron, D.; et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): Final overall survival analysis. Ann. Oncol. 2022, 33, 321–329. [Google Scholar] [CrossRef]
- O’Sullivan, C.C.; Ballman, K.V.; McCall, L.; Kommalapati, A.; Zemla, T.; Weiss, A.; Mitchell, M.; Blinder, V.; Tung, N.M.; Irvin, W.J.; et al. Alliance A011801 (compassHER2 RD): Postneoadjuvant T-DM1 + tucatinib/placebo in patients with residual HER2-positive invasive breast cancer. Future Oncol. 2021, 17, 4665–4676. [Google Scholar] [CrossRef]
- Bang, Y.J.; Giaccone, G.; Im, S.A.; Oh, D.Y.; Bauer, T.M.; Nordstrom, J.L.; Li, H.; Chichili, G.R.; Moore, P.A.; Hong, S.; et al. First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors. Ann. Oncol. 2017, 28, 855. [Google Scholar] [CrossRef]
- Rugo, H.S.; Im, S.A.; Cardoso, F.; Cortés, J.; Curigliano, G.; Musolino, A.; Pegram, M.D.; Wright, G.S.; Saura, C.; Escrivá-De-Romaní, S.; et al. Efficacy of Margetuximab vs. Trastuzumab in Patients with Pretreated ERBB2-Positive Advanced Breast Cancer: A Phase 3 Randomized Clinical Trial. JAMA Oncol. 2021, 7, 573–584. [Google Scholar] [CrossRef]
- Li, W.; Zhu, Z.; Chen, W.; Feng, Y.; Dimitrov, D.S. Crystallizable Fragment Glycoengineering for Therapeutic Antibodies Development. Front. Immunol. 2017, 8, 1554. [Google Scholar] [CrossRef]
- Coënon, L.; Villalba, M. From CD16a Biology to Antibody-Dependent Cell-Mediated Cytotoxicity Improvement. Front. Immunol. 2022, 13, 913215. [Google Scholar] [CrossRef] [PubMed]
- Rugo, H.S.; Im, S.A.; Cardoso, F.; Cortes, J.; Curigliano, G.; Musolino, A.; Pegram, M.D.; Bachelot, T.; Wright, G.S.; Saura, C.; et al. Margetuximab versus Trastuzumab in Patients with Previously Treated HER2-Positive Advanced Breast Cancer (SOPHIA): Final Overall Survival Results from a Randomized Phase 3 Trial. J. Clin. Oncol. 2023, 41, 198–205. [Google Scholar] [CrossRef] [PubMed]
- MARGetuximab or Trastuzumab (MARGOT). ClinicalTrials.gov. (n.d.). Available online: https://clinicaltrials.gov/ct2/show/NCT04425018?cond=Margetuximab+breast+cancer&draw=2&rank=5 (accessed on 16 May 2023).
- Xuhong, J.; Qi, X.; Tang, P.; Fan, L.; Chen, L.; Zhang, F.; Tan, X.; Yan, W.; Zhong, L.; He, C.; et al. Neoadjuvant Pyrotinib plus Trastuzumab and Chemotherapy for Stage I-III HER2-Positive Breast Cancer: A Phase II Clinical Trial. Oncologist 2020, 25, e1909–e1920. [Google Scholar] [CrossRef] [PubMed]
- Xu, B.; Yan, M.; Ma, F.; Hu, X.; Feng, J.; Ouyang, Q.; Tong, Z.; Li, H.; Zhang, Q.; Sun, T.; et al. Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): A multicentre, open-label, randomised, controlled, phase 3 trial. Lancet Oncol. 2021, 22, 351–360. [Google Scholar] [CrossRef] [PubMed]
- Yan, M.; Ouyang, Q.; Sun, T.; Niu, L.; Yang, J.; Li, L.; Song, Y.; Hao, C.; Chen, Z.; Orlandi, A.; et al. Pyrotinib plus capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases (PERMEATE): A multicentre, single-arm, two-cohort, phase 2 trial. Lancet Oncol. 2022, 23, 353–361. [Google Scholar] [CrossRef]
- Wu, J.; Jiang, Z.; Liu, Z.; Yang, B.; Yang, H.; Tang, J.; Wang, K.; Liu, Y.; Wang, H.; Fu, P.; et al. Neoadjuvant pyrotinib, trastuzumab, and docetaxel for HER2-positive breast cancer (PHEDRA): A double-blind, randomized phase 3 trial. BMC Med. 2022, 20, 498. [Google Scholar] [CrossRef]
- Yin, W.; Wang, Y.; Wu, Z.; Ye, Y.; Zhou, L.; Xu, S.; Lin, Y.; Du, Y.; Yan, T.; Yang, F.; et al. Neoadjuvant Trastuzumab and Pyrotinib for Locally Advanced HER2-Positive Breast Cancer (NeoATP): Primary Analysis of a Phase II Study. Clin. Cancer Res. 2022, 28, 3677–3685. [Google Scholar] [CrossRef] [PubMed]
- Pyrotinib, Trastuzumab, Pertuzumab and Nab-Paclitaxel as Neoadjuvant Therapy in HER2-Positive Breast Cancer. ClinicalTrials.gov. (n.d.). Available online: https://clinicaltrials.gov/ct2/show/NCT04398914?term=NCT04398914&draw=2&rank=1 (accessed on 9 May 2023).
- A Study of ARX788 Combined with Pyrotinib Maleate versus TCBHP (Trastuzumab Plus Pertuzumab with Docetaxel and Carboplatin) as Neoadjuvant Treatment in HER2-Positive Breast Cancer Patients. ClinicalTrials.gov. (n.d.). Available online: https://clinicaltrials.gov/ct2/show/NCT05426486?term=NCT05426486&draw=2&rank=1 (accessed on 9 May 2023).
- Piccart, M.J.; Hilbers, F.S.; Bliss, J.M.; Caballero, C.; Frank, E.S.; Renault, P.; Kaoudjt, R.N.; Schumacher, E.; Spears, P.A.; Regan, M.M.; et al. Road map to safe and well-designed de-escalation trials of systemic adjuvant therapy for solid tumors. J. Clin. Oncol. 2020, 38, 4120–4129. [Google Scholar] [CrossRef]
- Waks, A.G.; Desai, N.V.; Li, T.; Poorvu, P.D.; Partridge, A.H.; Sinclair, N.; Spring, L.M.; Faggen, M.; Constantine, M.; Metzger, O.; et al. A prospective trial of treatment de-escalation following neoadjuvant paclitaxel/trastuzumab/pertuzumab in HER2-positive breast cancer. Npj Breast Cancer 2022, 8, 63. [Google Scholar] [CrossRef]
- Debien, V.; Adam, V.; Caparica, R.; Fumagalli, D.; Velghe, C.; Gaye, J.; De Nobrega, V.C.; Arahmani, A.; Zoppoli, G.; Piccart-Gebhart, M.J. DECRESCENDO: De-escalation of adjuvant chemotherapy in patients with HER2+/HR-/node-negative early breast cancer who achieve pCR after neoadjuvant taxane and subcutaneous dual anti-HER2 blockade. J. Clin. Oncol. 2022, 40 (Suppl. S16), TPS621. [Google Scholar] [CrossRef]
- De-Escalation Adjuvant Chemo in HER2+/ER-/Node-neg Early BC Patients Who Achieved pCR after Neoadjuvant Chemo & Dual HER2 Blockade. ClinicalTrials.gov. (n.d.). Available online: https://clinicaltrials.gov/ct2/show/NCT04675827?term=DECRESCENDO+HER2&draw=2&rank=1 (accessed on 27 May 2023).
- CompassHER2-pCR: Decreasing Chemotherapy for Breast Cancer Patients after Pre-surgery Chemo and Targeted Therapy. ClinicalTrials.gov. (n.d.). Available online: https://clinicaltrials.gov/ct2/show/NCT04266249?term=CompassHER2+pCR+trial&draw=2&rank=1 (accessed on 31 May 2023).
- DAPHNe De-escalation HER2|Breast Cancer—List Results. ClinicalTrials.gov. (n.d.). Available online: https://clinicaltrials.gov/ct2/results?cond=Breast+Cancer&term=DAPHNe+De-escalation+HER2&cntry=&state=&city=&dist= (accessed on 31 May 2023).
- Pérez-García, J.M.; Gebhart, G.; Ruiz Borrego, M.; Stradella, A.; Bermejo, B.; Schmid, P.; Marmé, F.; Escrivá-de-Romani, S.; Calvo, L.; Ribelles, N.; et al. Chemotherapy de-escalation using an 18F-FDG-PET-based pathological response-adapted strategy in patients with HER2-positive early breast cancer (PHERGain): A multicentre, randomised, open-label, non-comparative, phase 2 trial. Lancet Oncol. 2021, 22, 858–871. [Google Scholar] [CrossRef] [PubMed]
- Cortes, J. ASCO 2023—Oral Abstract Session: 3-Year Invasive Disease-Free Survival (iDFS) of the Strategy-Based, Randomized Phase II PHERGain Trial Evaluating Chemotherapy (CT) De-escalation in Human Epidermal Growth Factor Receptor 2-Positive (HER2[+]) Early Breast Cancer (EBC). Available online: https://meetings.asco.org/abstracts-presentations/219848 (accessed on 5 June 2023).
- Vogt, P.K.; Hart, J.R.; Gymnopoulos, M.; Jiang, H.; Kang, S.; Bader, A.G.; Zhao, L.; Denley, A. Phosphatidylinositol 3-kinase (PI3K): The Oncoprotein. Curr. Top. Microbiol. Immunol. 2011, 347, 79. [Google Scholar] [CrossRef]
- Miricescu, D.; Totan, A.; Stanescu-Spinu, I.I.; Badoiu, S.C.; Stefani, C.; Greabu, M. PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects. Int. J. Mol. Sci. 2020, 22, 173. [Google Scholar] [CrossRef] [PubMed]
- Campone, M.; Bachelot, T.; Treilleux, I.; Pistilli, B.; Salleron, J.; Seegers, V.; Arnedos, M.; Loussouarn, D.; Wang, Q.; Vanlemmens, L.; et al. A phase II randomised study of preoperative trastuzumab alone or combined with everolimus in patients with early HER2-positive breast cancer and predictive biomarkers (RADHER trial). Eur. J. Cancer 2021, 158, 169–180. [Google Scholar] [CrossRef] [PubMed]
- Occhiuzzi, M.A.; Lico, G.; Ioele, G.; De Luca, M.; Garofalo, A.; Grande, F. Recent advances in PI3K/PKB/mTOR inhibitors as new anticancer agents. Eur. J. Med. Chem. 2023, 246, 114971. [Google Scholar] [CrossRef]
- Baselga, J.; Campone, M.; Piccart, M.; Burris, H.A.; Rugo, H.S.; Sahmoud, T.; Noguchi, S.; Gnant, M.; Pritchard, K.I.; Lebrun, F.; et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 2012, 366, 520–529. [Google Scholar] [CrossRef]
- Zhu, Y.; Zhang, X.; Liu, Y.; Zhang, S.; Liu, J.; Ma, Y.; Zhang, J. Antitumor effect of the mTOR inhibitor everolimus in combination with trastuzumab on human breast cancer stem cells in vitro and in vivo. Tumor Biol. 2012, 33, 1349–1362. [Google Scholar] [CrossRef]
- Seo, Y.; Park, Y.H.; Ahn, J.S.; Im, Y.H.; Nam, S.J.; Cho, S.Y.; Cho, E.Y. PIK3CA Mutations and Neoadjuvant Therapy Outcome in Patients with Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: A Sequential Analysis. J. Breast Cancer 2018, 21, 382. [Google Scholar] [CrossRef]
- Martínez-Saéz, O.; Chic, N.; Pascual, T.; Adamo, B.; Vidal, M.; González-Farré, B.; Sanfeliu, E.; Schettini, F.; Conte, B.; Brasó-Maristany, F.; et al. Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast Cancer Res. 2020, 22, 45. [Google Scholar] [CrossRef]
- Irelli, A.; Parisi, A.; D’orazio, C.; Sidoni, T.; Rotondaro, S.; Patruno, L.; Pavese, F.; Bafile, A.; Resta, V.; Pizzorno, L.; et al. Anthracycline-Free Neoadjuvant Treatment in Patients with HER2-Positive Breast Cancer: Real-Life Use of Pertuzumab, Trastuzumab and Taxanes Association with an Exploratory Analysis of PIK3CA Mutational Status. Cancers 2022, 14, 3003. [Google Scholar] [CrossRef]
- Kim, J.W.; Lim, A.R.; You, J.Y.; Lee, J.H.; Song, S.E.; Lee, N.K.; Jung, S.P.; Cho, K.R.; Kim, C.Y.; Park, K.H. PIK3CA Mutation is Associated with Poor Response to HER2-Targeted Therapy in Breast Cancer Patients. Cancer Res. Treat. 2023, 55, 531–541. [Google Scholar] [CrossRef] [PubMed]
- Baselga, J.; Phillips, G.D.L.; Verma, S.; Ro, J.; Huober, J.; Guardino, A.E.; Samant, M.K.; Olsen, S.; De Haas, S.L.; Pegram, M.D. Relationship between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer. Clin. Cancer Res. 2016, 22, 3755–3763. [Google Scholar] [CrossRef] [PubMed]
- Baselga, J.; Cortés, J.; Im, S.A.; Clark, E.; Ross, G.; Kiermaier, A.; Swain, S.M. Biomarker Analyses in CLEOPATRA: A phase III, placebo-controlled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-line metastatic breast cancer. J. Clin. Oncol. 2014, 32, 3753–3761. [Google Scholar] [CrossRef]
- Galstyan, A.; Cho, J.; Johnson, D.E.; Grandis, J.R. Modulation of the PI3K/mTOR pathways. In Improving the Therapeutic Ratio in Head and Neck Cancer; Elsevier: Amsterdam, The Netherlands, 2020; pp. 89–105. [Google Scholar] [CrossRef]
- André, F.; Ciruelos, E.M.; Juric, D.; Loibl, S.; Campone, M.; Mayer, I.A.; Rubovszky, G.; Yamashita, T.; Kaufman, B.; Lu, Y.S.; et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: Final overall survival results from SOLAR-1. Ann. Oncol. 2021, 32, 208–217. [Google Scholar] [CrossRef] [PubMed]
- Pérez-Fidalgo, J.A.; Criscitiello, C.; Carrasco, E.; Regan, M.M.; Di Leo, A.; Ribi, K.; Adam, V.; Bedard, P.L. A phase III trial of alpelisib + trastuzumab ± fulvestrant versus trastuzumab + chemotherapy in HER2+ PIK3CA-mutated breast cancer. Future Oncol. 2022, 18, 2339–2349. [Google Scholar] [CrossRef] [PubMed]
- Shi, Q.; Xuhong, J.; Tian, H.; Qu, M.; Zhang, Y.; Jiang, J.; Qi, X. Predictive and prognostic value of PIK3CA mutations in HER2-positive breast cancer treated with tyrosine kinase inhibitors: A systematic review and meta-analysis. Biochim. Biophys. Acta Rev. Cancer 2023, 1878, 188847. [Google Scholar] [CrossRef]
- Mercogliano, M.F.; Bruni, S.; Mauro, F.L.; Schillaci, R. Emerging Targeted Therapies for HER2-Positive Breast Cancer. Cancers 2023, 15, 1987. [Google Scholar] [CrossRef]
- Knutson, K.L.; Clynes, R.; Shreeder, B.; Yeramian, P.; Kemp, K.P.; Ballman, K.; Tenner, K.S.; Erskine, C.L.; Norton, N.; Northfelt, D.; et al. Improved Survival of HER2+ Breast Cancer Patients Treated with Trastuzumab and Chemotherapy Is Associated with Host Antibody Immunity against the HER2 Intracellular Domain. Cancer Res. 2016, 76, 3702–3710. [Google Scholar] [CrossRef]
- Disis, M.L.; Guthrie, K.A.; Liu, Y.; Coveler, A.L.; Higgins, D.M.; Childs, J.S.; Dang, Y.; Salazar, L.G. Safety and Outcomes of a Plasmid DNA Vaccine Encoding the ERBB2 Intracellular Domain in Patients with Advanced-Stage ERBB2-Positive Breast Cancer: A Phase 1 Nonrandomized Clinical Trial. JAMA Oncol. 2023, 9, 71–78. [Google Scholar] [CrossRef]
- Morse, M.A.; Crosby, E.J.; Force, J.; Osada, T.; Hobeika, A.C.; Hartman, Z.C.; Berglund, P.; Smith, J.; Lyerly, H.K. Clinical trials of self-replicating RNA-based cancer vaccines. Cancer Gene Ther. 2023, 2023, 803–811. [Google Scholar] [CrossRef]
- Kang, J.; Lee, H.J.; Lee, J.; Hong, J.; Hong Kim, Y.; Disis, M.L.; Gim, J.A.; Park, K.H. Novel peptide-based vaccine targeting heat shock protein 90 induces effective antitumor immunity in a HER2+ breast cancer murine model. J. Immunother. Cancer 2022, 10, e004702. [Google Scholar] [CrossRef] [PubMed]
- Crosby, E.J.; Gwin, W.; Blackwell, K.; Marcom, P.K.; Chang, S.; Maecker, H.T.; Broadwater, G.; Hyslop, T.; Kim, S.; Rogatko, A.; et al. Vaccine-induced memory CD8+ T cells provide clinical benefit in HER2 expressing breast cancer: A mouse to human translational study. Clin. Cancer Res. 2019, 25, 2725. [Google Scholar] [CrossRef]
- Ahmadzadeh, M.; Farshdari, F.; Nematollahi, L.; Behdani, M.; Mohit, E. Anti-HER2 scFv Expression in Escherichia coli SHuffle®T7 Express Cells: Effects on Solubility and Biological Activity. Mol. Biotechnol. 2020, 62, 18–30. [Google Scholar] [CrossRef] [PubMed]
- Ahmadzadeh, M.; Mohit, E. Therapeutic potential of a novel IP-10-(anti-HER2 scFv) fusion protein for the treatment of HER2-positive breast cancer. Biotechnol. Lett. 2023, 45, 371–385. [Google Scholar] [CrossRef] [PubMed]
- Ahmadzadeh, M.; Farshdari, F.; Behdani, M.; Nematollahi, L.; Mohit, E. Cloning, Expression and One-Step Purification of a Novel IP-10-(anti-HER2 scFv) Fusion Protein in Escherichia coli. Int. J. Pept. Res. Ther. 2021, 27, 433–446. [Google Scholar] [CrossRef]
- Trudeau, M.; Fraser, B. The CADTH pCODR Expert Review Committee Process Explained. Comment on Rayson et al. Access to Neoadjuvant Pertuzumab for HER2 Positive Breast Cancer in Canada: A Dilemma Increasingly Difficult to Explain. Curr. Oncol. 2022, 29, 9891–9895. Curr. Oncol. 2023, 30, 5047–5049. [Google Scholar] [CrossRef]
Study | Interval | Recurrence Outcome (95% CI) | Survival Outcome (95% CI) |
---|---|---|---|
Low-Risk HER2+ | |||
Hassing et al. (2023) [58], a meta-analysis of 12 trials (n = 6927) Setting: adjuvant. Population: T1abN0 Treatment: 1. Trastuzumab and Cht 2. No trastuzumab ± Cht | 5 years | Group 1 vs. 2 DFS, HR 0.14 (0.07–0.29); p < 0.0001 Group 1: DFS of 95.3% (92.7–97.9) Group 2: DFS of 88.3% (84.8–91.8) | Group 1 vs. 2 OS, HR 0.17 (0.04–0.66); p = 0.011 Group 1: OS of 98.5% (97.2–99.8) Group 2: OS of 95.9% (94.2–97.6) |
O’Sullivan et al. (2015) [60], a meta-analysis of five trials (n = 2263) Setting: adjuvant. Population *: T1 N0–1 Treatment: taxane-based Cht with vs. without trastuzumab * 87% of patients had LN = 0 | 8 years | ER+: DFS, HR 0.70 (0.59–0.85); p < 0.001 ER−: DFS, HR 0.66 (0.49–0.88); p < 0.001 Recurrence rate: ER+: 17.3% vs. 24.3%; p < 0.001 ER−: 24.0% vs. 33.4%; p < 0.001 | ER+: OS, HR 0.68 (0.52–0.89); p = 0.006 ER−: OS, HR 0.59 (0.47–0.74); p < 0.001 Mortality rate: ER+: 7.8% vs. 11.6%; p = 0.005 ER−: 12.4% vs. 21.2%; p < 0.001 |
APT (2019) [62], a phase II, single-arm trial (n = 406) Setting: adjuvant. Population: T1–T2 (≤3 cm) N0 Treatment: TH (trastuzumab weekly paclitaxel × 12) | 7 years | DFS of 93.3% (90.4–96.2%) | OS of 95% (92.4–97.7) |
ATEMPT (2021) [64], a phase III trial (n = 497) Setting: adjuvant. Population: T1abcN0 Treatment: 17 cycles of T-DM1 vs. TH (weekly paclitaxel × 12 and trastuzumab for 1 year) | 3 years | iDFS of 97.8% vs. 93.4%; p < 0.0001. RFI of 99.2% (98.2–100) vs. 94.3% (89.2–98.8) | – |
High-Risk HER2+ | |||
Joint analysis of the phase III NSABP B-31 and NCCTG N983 trials, Perez et al. (2014) [29] (n = 4046) Setting: adjuvant. Population: any LN+, ER+ ≥ T2 N0, or ER− ≥ T1cN0 Treatment: AC→T with vs. without trastuzumab | 10 years | DFS, HR 0.60 (0.53–0.68); p < 0.001 DFS of 73.7% vs. 62.2% ER+: DFS of 76.1% vs. 65.1% ER−: DFS of 70.9% vs. 58.6% | OS, HR 0.63 (0.54–0.73); p < 0.001 OS of 84% vs. 75.2% ER+: OS of 86% vs. 77.1% ER−: OS of 81.6% vs. 73% |
NOAH (2014) [70], a phase III trial (n = 235) Setting: neoadjuvant. Population: stage II–III LN+ Treatment: anthracycline-based Cht with vs. without trastuzumab | 5 years | EFS, HR 0.65 (0.45–0.95); p = 0.024 EFS of 58% (48–66) vs. 43% (34–52) | OS, HR 0.68 (0.44–1.05); p = 0.083 OS of 74% (64–81) vs. 63% (53–71) |
Dual Anti-HER2 blockage | |||
APHINITY (2017) [67], (2022) [68], a phase III trial (n = 4805) Setting: adjuvant. Population: T1–3 LN+ or LN– and high-risk (T > 2 cm) Treatment: anthracycline-based Cht with H+P vs. trastuzumab alone | 6 years 8 years | LN+: IDFS, HR 0.72 (0.59–0.87) IDFS, HR 0.77 (0.66–0.91) IDFS of 88.4% vs. 85.8% | – OS, HR 0.83 (0.68–1.02); p = 0.078 OS of 92.7% vs. 92.0% |
KAITLIN (2022) [69], a phase III trial (n = 1846) Setting: adjuvant. Population *: LN+, ER+: T1–3 or ER-: T2–3 Treatment: AC→TH+P vs. AC→TDM1+ P * 89.8% of the population had LN+ | 3 years | IDFS of 94.2% vs. 93.1% LN+: HR 0.97 (0.71–1.32; p = 0.83) | – |
NeoSphere (2012) [72], a phase II trial (n = 417) Setting: neoadjuvant. Population: T2–3 N0–3 or T4a-c LN+ or LN– Treatment *: Group A: TH. Group B: TH+P. Group C: H+P. Group D: TP * Patients received FEC + trastuzumab in an adjuvant setting | 5 years | PFS, group A: 81% (72–88), group B: 84% (72 –91), group C: 80% (70–86), and group D: 75% (64–83) All groups combined: pCR vs. pRD: PFS of 85% vs. 76%, HR 0.54 (0.29–1.00) | – |
KRISTINE (2018) [74] (2019) [75], a phase II trial (n = 444) Setting: neoadjuvant and adjuvant. Population: stage II–III, (T > 2 cm) Treatment: (N)T-DM1+P → (A)T-DM1+P vs. (N)TCH+P → (A)H+P | 3 years | pCR rate of 44.4% vs. 55.7%; p = 0.016 EFS, HR 2.61 (1.36–4.98) EFS of 85.3% vs. 94.2% | – |
Guarneri et al. (2022) [76], a meta-analysis of four trials (n = 1410) Setting: neoadjuvant. Population: stage I–III Treatment: Cht and trastuzumab, lapatinib, or both combined | 6–7 years | H+L: RFS, HR 0.62 (0.46–0.85) All groups combined: pCR sub-group: RFS, HR 0.45 (0.34–0.60) | H+L: OS, HR 0.65 (0.43–0.98) All groups combined: pCR sub-group: OS, HR 0.32 (0.22–0.48) |
Adjuvant HER2 therapy in postoperative pathologic residual disease | |||
KATHERINE (2019) [80], a phase III trial (n = 1486) Setting: adjuvant. Population: stages I–IIIc (except T1aN0 or T1bN0). All patients had pRD and received taxane-based NAC * with HER2 therapy Treatment: TDM-1 versus trastuzumab * 76.9% of patients received Cht with anthracycline; 18.3% received H+P in a neoadjuvant setting | 3 years | DFS, HR 0.50 (0.39–0.64); p < 0.001 | OS, HR 0.70 (0.47–1.05); p = 0.08 |
ExteNET (2021) [83] (2022) [84], phase III trial (n = 2840) Setting: adjuvant. Population: stages I–IIIc Treatment: after the completion of Cht and trastuzumab, the patients received adjuvant neratinib for 1 year or placebo | 5 years 5 and 8 years | iDFS, HR 0.60 (0.33–1.07) iDFS of 90.2% vs. 87.7% − At 5 years:DDFS, HR 0.57 (0.39–0.83) DDFS of 92.4% vs. 87.7% (84.8–90.1) | − At 8 years: OS, HR 0.95 (0.75–1.21) OS, ER+ group: HR 0.80 (0.58–1.11) OS, ER− group: HR 1.18 (0.83–1.69) |
Chemotherapy with vs. without Anthracycline | |||
TRAIN-2 (2018) [85], a phase III trial (n = 408) Setting: neoadjuvant. Population: stage II–III Treatment: Cht, trastuzumab, and pertuzumab with vs. without anthracycline | 3 years | PCR rate of 67% vs. 68%; p = 0.95 EFS, HR 0.90 (0.50–1.63) EFS of 92.7% vs. 93.6%, | OS, HR 0.91 (0.35–2.36) OS of 97.7% vs. 98.2% |
BCIRG 006 (2011) [35] (2016) [87], a phase III trial (n = 3222) Setting: adjuvant. Population *: T1–3 LN+ or high-risk with LN– Treatment: group A: AC→T, group B: AC→TH and group C: TCH * 72% of patients had LN+ | 10 years | DFS, group B: AC→TH HR 0.70, (0.60–0.83); p < 0.001 DFS, group C: TCH HR 0.76 (0.65–0.90); p < 0.001 | OS, group B: AC→TH HR 0.64 (0.52–0.79); p < 0.001 OS group C: TCH HR 0.76 (0.62–0.93); p = 0.0081 |
Zhu et al. (2023) [88], a meta-analysis of 11 trials (n = 1998) Setting: neoadjuvant. Population: operable breast cancer Treatment: Cht, trastuzumab ± pertuzumab with vs. without anthracycline | – | pCR OR 0.95 (0.61–1.48); p = 0.83 | – |
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Giffoni de Mello Morais Mata, D.; Chehade, R.; Hannouf, M.B.; Raphael, J.; Blanchette, P.; Al-Humiqani, A.; Ray, M. Appraisal of Systemic Treatment Strategies in Early HER2-Positive Breast Cancer—A Literature Review. Cancers 2023, 15, 4336. https://doi.org/10.3390/cancers15174336
Giffoni de Mello Morais Mata D, Chehade R, Hannouf MB, Raphael J, Blanchette P, Al-Humiqani A, Ray M. Appraisal of Systemic Treatment Strategies in Early HER2-Positive Breast Cancer—A Literature Review. Cancers. 2023; 15(17):4336. https://doi.org/10.3390/cancers15174336
Chicago/Turabian StyleGiffoni de Mello Morais Mata, Danilo, Rania Chehade, Malek B. Hannouf, Jacques Raphael, Phillip Blanchette, Abdullah Al-Humiqani, and Monali Ray. 2023. "Appraisal of Systemic Treatment Strategies in Early HER2-Positive Breast Cancer—A Literature Review" Cancers 15, no. 17: 4336. https://doi.org/10.3390/cancers15174336
APA StyleGiffoni de Mello Morais Mata, D., Chehade, R., Hannouf, M. B., Raphael, J., Blanchette, P., Al-Humiqani, A., & Ray, M. (2023). Appraisal of Systemic Treatment Strategies in Early HER2-Positive Breast Cancer—A Literature Review. Cancers, 15(17), 4336. https://doi.org/10.3390/cancers15174336