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Table of Contents
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 80-83

Innovativeness in breast cancer: The prime example of anti-HER2 agents

1 Medical Oncology Department, University Hospital Waterford, Waterford, Ireland
2 Medical Oncology Department, Sligo University Hospital, Sligo, Ireland

Date of Web Publication31-Dec-2018

Correspondence Address:
Yasar Ahmed
Medical Oncology Department, University Hospital Waterford, Dunmore Road, Waterford, X91 ER8E
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JCO.JCO_15_18

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Since the identification of HER2 in breast cancer pathogenesis and the introduction of the first drugs targeting this receptor, the humanized monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib, many advances have been made in the treatment of HER2-positive breast cancer that have led to a progressive improvement in the outcome of patients with early and advanced breast cancer. One of the major achievements is the development of dual HER2 blockade strategies. Evidence from the neoadjuvant and metastatic setting suggests that by combining trastuzumab with other anti-HER2 drugs such as lapatinib or the humanized monoclonal antibody pertuzumab, the efficacy of treatment may be further improved.

Keywords: Breast cancer, HER2, lapatinib, pertuzumab, trastuzumab

How to cite this article:
Ahmed Y, Lee J, Yousif A. Innovativeness in breast cancer: The prime example of anti-HER2 agents. J Curr Oncol 2018;1:80-3

How to cite this URL:
Ahmed Y, Lee J, Yousif A. Innovativeness in breast cancer: The prime example of anti-HER2 agents. J Curr Oncol [serial online] 2018 [cited 2024 Feb 28];1:80-3. Available from: http://www.https://journalofcurrentoncology.org//text.asp?2018/1/2/80/249054

  Anti-HER2 in Neoadjuvant Setting Top

In the neoadjuvant setting, chemotherapy combined with trastuzumab and pertuzumab or lapatinib increased pathological complete response (pCR) rates compared with chemotherapy plus single anti-HER2 agent in various prospective studies.[1],[2],[3] In the metastatic setting, the first-line combination of docetaxel, trastuzumab, and pertuzumab results in an impressive improvement in both progression free (median, 12.4 vs. 18.5 months) and overall survival (OS) (median, 40.8 vs. 56.5 months) of the patients compared with chemotherapy plus trastuzumab.[4],[5]

Moreover, the chemotherapy-antibody conjugate, trastuzumab emtansine (T-DM1), was able to significantly prolong the survival of patients with advanced breast cancer previously treated with a taxane and trastuzumab compared with capecitabine plus lapatinib.[6] However, despite these advances, treatment optimization has not been achieved yet.

Indeed, a proportion of patients with early breast cancer eventually relapse and all patients treated in the advanced setting develop resistance to anti-HER2 agents at some point. However, in the early setting, not all HER2-positive patients deserve the most effective treatment as a high proportion of them are already cured by less intensive approaches. Given the increasing availability of new anti-HER2 agents, patients’ selection on the basis of clinicopathologic factors and molecular biomarkers will be crucial to define optimal strategies for treatment personalization.

The analysis of the results of the recent adjuvant ALTTO trial, which apparently contrast with the results of neoadjuvant trials testing dual HER2 blockade, perfectly fits this discussion and highlights the need to test different treatment approaches for patients with high-risk and low-risk HER2-positive breast cancer.

pCR is associated with good outcome and is considered a valid surrogate of treatment efficacy.[7],[8] The Food and Drug Administration (FDA) has recently approved the neoadjuvant combination of docetaxel, pertuzumab, and trastuzumab on the basis of the results of a single four-arm randomized phase II trial (NeoSphere) that showed a significant improvement in pCR rate for patients treated with docetaxel plus pertuzumab plus trastuzumab (45.8%) compared to patients treated with docetaxel and trastuzumab (29%, P = 0.0141).[3],[9]

Probably the best approach in terms of OS gain in the neoadjuvant setting is combining trastuzumab with either pertuzumab or lapatinib. Although dual anti-HER2 agents seem to be superior to single HER2 blockade in the neoadjuvant setting, it will be critical to follow the survival data on long-term basis of these trials.[1],[10]

The neoadjuvant NeoALTTO trial showed similar significant pCR improvement with chemotherapy plus trastuzumab and lapatinib versus chemotherapy plus trastuzumab (51.3% vs. 29.5%, P = 0.0001).[1] However, the ALTTO trial, which randomized 8381 patients to receive adjuvant chemotherapy combined with trastuzumab, lapatinib (arm closed in 2011), concomitant trastuzumab and lapatinib, or sequential trastuzumab and lapatinib, failed to show a superiority of the dual blockade strategy. Disease-free survival rates for the concomitant trastuzumab plus lapatinib and the trastuzumab arm were similar (88% and 86%, respectively).[11] These discrepancies between the results of the neoadjuvant and the adjuvant trials may be explained by the difference in outcomes and patient populations.

pCR is considered a surrogate end point for survival as it has been shown that patients achieving a pCR experience a better prognosis compared to patients with residual disease.

However, no threshold has been defined for the association between increased pCR and improved survival. Indeed, not all patients with pCR remain free of disease and not all patients with residual disease will eventually relapse, as shown for example in survival curves according to pCR from the NeoALTTO study.[12]

Second, the populations of patients treated in the neoadjuvant and in the adjuvant settings differ. As an example, more than half of the patients included in the NeoALTTO trial were node positive and 42% had tumors larger than 5 cm.[1] In such high-risk population, it is more likely to see an advantage from the administration of more effective treatments. To the opposite, 40% of the patients included in the ALTTO study were node negative and 45% had tumors smaller than 2cm, reflecting a lower risk population. Indeed, the control arm of the ALTTO trial was associated with an optimal performance in terms of survival, with 94% of the patients alive at 4 years.[11]

In such conditions, it is more unlikely to see any benefit from the addition of novel therapies to current standard adjuvant treatment. It is noteworthy that the “real-world” population with patients of HER2-positive breast cancer that receive adjuvant treatment is more superimposable in terms of clinicopathologic characteristics to the one included in the ALTTO trial and in other recent adjuvant trials than the population of patients included in early adjuvant trastuzumab studies.

The fact that most of these “real-world” patients are already cured by standard treatment suggests that no or only minimal improvement can be obtained by treatment intensification.

Stratification of patients on the basis of molecular biomarkers holds promises. In addition, development of predictive biomarkers would be valuable to help identify patients who may benefit from dual anti-HER2 treatment, allowing for a truly personalized treatment framework.

Different mechanisms of sensitivity or resistance to anti-HER2 agents have been studied, mainly in the context of neoadjuvant trials. Recently, PIK3CA mutations have been shown to predict resistance to neoadjuvant chemotherapy plus anti-HER2 treatments. This is particularly evident when dual anti-HER2 agents are combined with chemotherapy.[13],[14] In addition, the immune system seems also to be an important modulator of sensitivity to anti-HER2 therapies.[15]

In a recent meta-analysis of neoadjuvant therapy for HER2-positive early breast cancer, the pooled response rate showed that PIK3CA mutation is associated with pCR in unselected HER2-positive patients, thus the predictive value of PIK3CA status may be stronger in those administered dual-targeting therapy and in HER2-positive/hormone receptor-positive patients.[2],[16]

Tumor-infiltrating lymphocytes are associated with higher pCR rates after chemotherapy plus anti-HER2 agents. In particular, in the analysis of the Cher-LOB trial, the highest pCR rate was observed for those patients with a high tumor infiltration by lymphocytes who were treated with chemotherapy, lapatinib and trastuzumab (83%).[17]

In advanced HER2-positive disease, tumor-infiltrating lymphocytes are significantly associated with prognosis with effects stronger for OS than progression free survival. This suggests that the influence of antitumor immunity persists in the advanced first-line setting and that the enhancement by immunotherapeutic approaches could possibly further improve survival.[3],[18] However, the role of tumor infiltrating lymphocytes in HER2-positive disease needs to be further evaluated, as the recent results of the analysis conducted within the N9831 trial suggest that in case of a lymphocyte-predominant breast cancer, the prognosis is good irrespective of whether trastuzumab is administered.[19]

In conclusion, more and more targeted strategies are or will be available, and patients’ selection for treatment personalization will be the key issue to offer the most effective treatment to patients more likely to derive benefit and to avoid unnecessary intensive approaches for those patients who do not need it.

A structured and logical approach, inspired by the principle of treatment personalization, to design trials testing the integration of novel drugs is warranted to avoid resources waste and to optimize patients’ outcome. Several scenarios may be identified. First, for patients presenting high-risk features (node positive, large tumors, aggressive disease), attempts to increase pCR rates by including new agents in the current standard neoadjuvant approach should be warranted. This approach would allow a fast evaluation of the efficacy of new treatments and speed up the approval and therefore facilitate the availability of effective drugs.

  Anti-HER2 in Post-Neoadjuvant Setting Top

The second scenario is the post-neoadjuvant setting. By considering pCR as a surrogate of treatment efficacy, two open questions remain to be answered. First, is it necessary to continue anti-HER2 treatment up to 1 year for patients with pCR at definitive surgery?

Second, should we offer more to those patients with less than pCR?

Trials addressing this issue are needed. One example is the ongoing Katherine study (NCT01772472), which is randomizing HER2-positive patients with less than pCR after neoadjuvant chemotherapy plus anti-HER2 to continue trastuzumab or T-DM1 for up to 1 year.

The third scenario includes those patients with small, node-negative tumors, treated upfront with surgery, who receive systemic adjuvant treatment. The availability of new biological anti-HER2 agents should better allow to de-escalate rather than intensify adjuvant treatment for this population, to spare unnecessary toxicity. Shorter HER2 treatment durations, anthracycline-free regimens, and combined anti-HER2 and hormonal chemotherapy-free therapies for HER2-positive and hormone-receptor-positive patients represent only some of the attempts for treatment de-escalation that either have been, or are being, or should be explored in clinical trials.[20],[21],[22]

The use of dual anti-HER2 adjuvant therapy should be restricted to patients with large tumors, multiple positive nodes, and negative hormone receptors. The benefit regarding invasive disease-free survival (IDFS) for addition of pertuzumab to trastuzumab in the APHINITY trial was limited (3-year overall IDFS is 94%, absolute benefit 0.9%). However, the absolute benefit was 1.6% in hormone-receptor-negative patients and 1.8% in patients with node-positive disease.[4],[23]

Finally, the implementation of biomarkers of sensitivity or resistance would hopefully permit to select the most effective regimen for each specific patient.[24]

Advances are being made today, which will continue to personalize therapy for this type of breast cancer. A better understanding of resistance to currently existing anti-HER2 agents and of the role played by the microenvironment (e.g., immune system) and of interconnected signaling pathways is at the core of clinical trials exploring new drugs and new regimens.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, et al.; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): A randomised, open-label, multicentre, phase 3 trial. Lancet 2012;379:633-40.  Back to cited text no. 1
Guarneri V, Frassoldati A, Bottini A, Cagossi K, Bisagni G, Sarti S, et al. Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: Results of the randomized phase II CHER-LOB study. J Clin Oncol 2012;30:1989-95.  Back to cited text no. 2
Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, 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.  Back to cited text no. 3
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Guarneri V, Dieci MV, Carbognin L, Maiorana A, Bettelli S, Tortora G, et al. Activity of neoadjuvant lapatinib (L) plus trastuzumab (T) for early breast cancer (EBC) according to PIK3CA mutations: Pathological complete response (pCR) rate in the CherLOB study and pooled analysis of randomized trials. Presented in the ESMO Meeting, Madrid, Spain, September 26–30, 2014. (Abstract 254O).  Back to cited text no. 14
Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, et al. Tumor infiltrating lymphocytes (TILs) indicate trastuzumab benefit in early-stage HER2-positive breast cancer (HER2+ BC). Presented in the 36th San Antonio Breast Cancer Symposium, San Antonio, Texas (USA), December 2013.  Back to cited text no. 15
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Dieci MV, Bisagni G, Cagossi K, Bottini A, Sarti S, Piacentini F, et al. Tumor infiltrating lymphocytes and correlation with outcome in the Cher-LOB study. Presented in the 37th San Antonio Breast Cancer Symposium, San Antonio, Texas (USA), December 2014. Abstract PD1-1.  Back to cited text no. 17
Luen S, Salgado R, Stephen F, Peter S, Jennifer E-W, Emma C, et al. Abstract S1-08: Prognostic associations of tumor-infiltrating lymphocytes (TIL) in metastatic HER2-positive breast cancer (BC) treated with trastuzumab and pertuzumab: A secondary analysis of the CLEOPATRA study. Cancer Res. 2017;77:S1-08.  Back to cited text no. 18
Perez EA, Ballman KV, Anderson SK, Thompson EA, Badve SS, Bailey H, et al. Stromal tumor-infiltrating lymphocytes(S-TILs): In the alliance N9831 trial S-TILs are associated with chemotherapy benefit but not associated with trastuzumab benefit. Presented in the 37th San Antonio Breast Cancer Symposium, San Antonio, Texas (USA), December 2014. Abstract S1-06.  Back to cited text no. 19
Guarneri V, Frassoldati A, Bruzzi P, D’Amico R, Belfiglio M, Molino A, et al. Multicentric, randomized phase III trial of two different adjuvant chemotherapy regimens plus three versus twelve months of trastuzumab in patients with HER2- positive breast cancer (short-HER trial; NCT00629278). Clin Breast Cancer 2008;8:453-6.  Back to cited text no. 20
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