the JCO editorial:
© 2013 by American Society of Clinical Oncology
Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade and Hormonal Therapy for the Treatment of Primary HER2-Positive Breast Cancer: One More Step Toward Chemotherapy-Free Therapy
Aleix Prat and
José Baselga⇑
+ Author Affiliations
Vall d'Hebron Institute of Oncology, Barcelona, Spain
Memorial Sloan-Kettering Cancer Center, New York, NY
Corresponding author: José Baselga, MD, PhD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; e-mail:
baselgaj@mskcc.org.
During the last decade, the introduction of agents that target the human epidermal growth factor receptor 2 (HER2), such as the monoclonal antibody trastuzumab (Herceptin; Roche, Basel, Switzerland) or the tyrosine kinase inhibitor lapatinib (Tykerb; GlaxoSmithKline, Research Triangle Park, NC), in combination with chemotherapy, has changed the course of HER2-positive breast cancer. In the metastatic setting, the addition of trastuzumab to taxanes increases progression-free survival (PFS) and overall survival (OS),1,2 whereas the addition of lapatinib to capecitabine increases PFS after treatment with regimens that include an anthracycline, a taxane, and trastuzumab.3 In the adjuvant setting, trastuzumab increases disease-free survival and OS.4,5
In addition to these impressive advances, clinical research to improve the outcome in HER2-positive breast cancer is as vibrant as it has ever been. A number of important questions are being addressed at this time, including the delineation of the role of neoadjuvant (presurgical) therapy, the concept of dual HER2 receptor blockade, the identification of markers of sensitivity or resistance to therapy, and, finally, the study of new agents. As reported in the article that accompanies this editorial, the timely Neoadjuvant Translational Breast Cancer Research Consortium 006 (TBCRC 006) trial by Rimawi et al6 has addressed three of these questions and has identified one more piece in the puzzle: the importance of adding hormonal therapy in the subset of patients with HER2-positive/hormone receptor (HR) –positive tumors.
To place this study in context, let us look at what we know today. In the neoadjuvant setting, the addition of trastuzumab to chemotherapy and maintenance for 1 year increases pathologic complete response (pCR) rates and 3-year event-free survival (EFS).7 And there is increasing evidence that there is a good correlation between pCR and EFS in HER2-positive disease,8 which has led to the acceptance of pCR as the primary end point in a number of neoadjuvant studies.9–12 If some of these studies, such as the Neo-Adjuvant Lapatinib and/or Trastuzumab Treatment Organisation (NeoALTTO) study,9 further confirm that pCR is a surrogate marker of EFS, improved pCR in HER2-positive breast cancer could lead to regulatory approval of novel agents in this disease.13
In terms of dual HER2 blockade, laboratory studies have shown that a more complete blockage of the HER2 and/or the HER signaling pathway by combining two or three inhibitors with nonoverlapping mechanisms of action improves cell death and tumor shrinkage in HER2-positive models.14–17 These preclinical findings have now been confirmed in the clinical setting. Trastuzumab and lapatinib (or trastuzumab and pertuzumab [Perjeta; Genentech, South San Francisco, CA], a humanized monoclonal antibody binding to the HER2 dimerization domain), in combination with chemotherapy, results in pCR rates of 45.8% to 51.3% compared with pCR rates of 24.0% to 29.5% with a single anti-HER2 agent combined with the same chemotherapy schedule.9–11 Moreover, the addition of pertuzumab to trastuzumab and docetaxel increases PFS and OS in first-line metastatic HER2-positive disease.18,19 These results have led to regulatory approval of pertuzumab and have placed the dual HER2 blockade with pertuzumab and trastuzumab in combination with chemotherapy as the standard of care in first-line metastatic disease. Furthermore, dual HER2 blockade strategies could also become standard of care in other settings. For example, the ongoing Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO)20 phase III trial is evaluating the adjuvant dual HER2 blockade with trastuzumab and lapatinib after chemotherapy, and A Study of Pertuzumab in Addition to Chemotherapy and Herceptin (Trastuzumab) As Adjuvant Therapy in Patients With HER2-Positive Primary Breast Cancer (APHINITY),21 a phase III trial, is also currently evaluating adjuvant trastuzumab and pertuzumab with chemotherapy.
Given that the dual HER2 blockade is more efficacious that single-agent HER2 therapy, a question that arises is whether the dual blockade may eliminate the need for chemotherapy in a subset of patients. In support of this proposal, the dual HER2 blockade without chemotherapy has shown high activity in a group of patients with metastatic and primary HER2-positive breast cancer.11,22,23 In HER2-positive metastatic breast cancer that was previously treated with trastuzumab, the addition of pertuzumab or lapatinib to trastuzumab showed higher clinical benefit than either pertuzumab or lapatinib alone.22,23 In treatment-naïve primary HER2-positive breast cancer, the chemotherapy-free trastuzumab-and-pertuzumab combination in the Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation (NeoSphere) trial achieved a pCR rate of 16.8% (18 of 107 patients) in the breast after 12 weeks of neoadjuvant treatment.11 Overall, these results suggest that a subset of patients with HER2-positive breast cancers is sensitive to the dual HER2 blockade and potentially could be treated without cytotoxic therapy.
The results of the TBCRC 006 trial reported by Rimawi et al6 further support this hypothesis. In this study, 66 patients with primary HER2-positive breast cancer were treated with trastuzumab and lapatinib without chemotherapy for 12 weeks in the neoadjuvant setting. The primary goal was pCR rate in the breast. Compared with the NeoSphere trial, patients with estrogen receptor (ER) –positive disease also received endocrine therapy. Notably, this was a patient population with particularly poor prognostic features: 52% of patients were age 50 years or younger at diagnosis, and 62% of patients had stage III disease (ie, > 5.0 cm). Although this was a small, single-arm study, the overall pCR rate of 27.0% is promising. Taken together, the results of the NeoSphere chemotherapy-free arm11 and the TBCRC 006 trial,6 totaling 173 patients, suggest that the dual HER2 blockade might eradicate all tumor cells in a substantial number of patients (approximately 25%) with primary HER2-positive breast cancer. More importantly, if these patients could be identified at diagnosis, they could avoid the short- and long-term toxicities that are associated with cytotoxic-based treatments.
On the basis of the current data, are we ready to implement a dual HER2 blockade and chemotherapy-free treatment strategy for primary HER2-positive breast cancer? The answer, outside of well-conducted clinical trials, is that we are not yet ready because there are several issues that need to be resolved. First, as of today, we do not have a biomarker that clearly identifies those patients who are more likely to achieve a pCR after the dual HER2 blockade alone. Second, chemotherapy is highly efficacious in HER2-positive tumors; that is, the addition of a single cytotoxic drug (ie, taxanes) to the dual HER2 blockade increases pCR rates almost three-fold (from 16.8% to 45.8% in the NeoSphere trial).11 In this regard, well-tolerated antibody-drug conjugates such as trastuzumab emtansine, which consists of trastuzumab linked to the cytotoxic agent mertansine, might prove to have similar activity (in combination with pertuzumab) as the combination of docetaxel, trastuzumab, and pertuzumab.24 Third, we need additional clinical studies that confirm the correlation between pCR and EFS. This is a question that is likely to be answered by the NeoALTTO study, given that the same anti-HER2 therapy as in the neoadjuvant part of the study was given for a total of 1 year in the adjuvant setting.
In any case, the ultimate decision to withhold effective chemotherapy would require a biomarker, or alternatively, a combination of biomarkers, that identifies these patients with a high specificity and a high positive predictive value. A number of biomarkers of response and/or resistance to single anti-HER2 therapies are currently being tested for validation purposes (eg, p95HER2,25 phosphatase and tensin homolog inactivation,26 cyclin E1 amplification,27 and PIK3CA mutations28). We do anticipate that these studies will shed some light. For example, in the Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study of docetaxel and trastuzumab with or without pertuzumab, although HER2 overexpression was the sole marker that was predictive of pertuzumab benefit, patients with high levels of HER2 protein and mRNA, HER3 mRNA, and wild-type PIK3CA had a better prognosis overall, which indeed suggests the presence of subgroups within the spectrum of HER2 breast cancer.29 In this regard, the study by Rimawi et al6 reminds us that one of the most consistent biomarkers of response and/or benefit to the dual HER2 blockade is still HR status. For example, the pCR rates of the chemotherapy- and endocrine-free trastuzumab and pertuzumab arm of the NeoSphere trial were 5.9% and 27.3% in patients with HR-positive and HR-negative tumors, respectively.11 These data clearly indicate that the different likelihood of response according to HR status is an intrinsic characteristic of tumors and not just a result of the known differential effect of chemotherapy in HR-positive and HR-negative disease. Interestingly, the pCR rate of patients with HR-positive disease treated with the dual HER2 blockade in combination with endocrine therapy in the TBCRC 006 trial was 3.5-fold higher than the pCR rate in the NeoSphere chemotherapy- and endocrine-free arm (21.0%6 v 5.9%11) and more similar to the pCR rates of HR-negative tumors treated with trastuzumab/pertuzumab alone (36.0% in TBCRC 0066 and 27.3% in NeoSphere11) or the pCR rates of HR-positive tumors treated with trastuzumab/pertuzumab and docetaxel (26.0%11). Given that pCR after endocrine therapy alone, or the dual HER2 blockade alone, is an infrequent event in HER2-positive/HR-positive disease, the 21.0% pCR rate after dual HER2 blockade and endocrine therapy can only be interpreted as a confirmation of the cross talk between HER2 and the estrogen receptor that has been elegantly demonstrated by the same authors and others in preclinical models.30,31 This observation is clearly one of the most important of the current study and indicates the importance of blocking the ER as well in HER2-positive/ER-positive tumors in future studies.
However, the biologic heterogeneity displayed by HR status in HER2-positive breast cancer is reflected at the molecular level. For example, gene expression analyses within HER2-positive disease identify all of the main intrinsic molecular subtypes of breast cancer (luminal A, luminal B, HER2 enriched [HER2-E], and basal like) but the HER2-E subtype, largely HR negative, and the luminal A and B subtypes, largely HR positive, predominate. Among them, the HER2-E subtype is characterized by the high expression of HER2-regulated genes and cell cycle–related genes, together with lower expression of luminal-related genes compared with the luminal A and B subtypes.32,33 Thus, the HER2-E subtype is likely to be the subtype with the highest activation of the epidermal growth factor receptor/HER2 pathway. Concordant with this, The Cancer Genome Atlas has reported that the vast majority of HER2-positive tumors of the HER2-E subtype show high amplification of the HER2 gene and overexpression of HER2 and epidermal growth factor receptor proteins.34 In addition to checking the currently HER2-positive subtypes described, a next-generation tumor sequencing effort may also identify determinants of exquisite sensitivity to anti-HER2 therapy. This approach has been fruitful in other instances, such as with mammalian target of rapamycin inhibitors in bladder cancer, in which a whole-genome sequencing effort in a patient with an exceptional response identified the presence of a tuberous sclerosis 1 mutation.35 A similar approach is clearly warranted in hypersensitive HER2-positive tumors.
In summary, the study by Rimawi et al6 has confirmed that a sizable subset of patients with HER2-positive tumors achieve pCR with a dual HER2 blockade without chemotherapy and that, in HER2-positive/ER-positive tumors, the addition of hormonal therapy to the dual HER2 blockade results in a pCR rate as high as historical controls with chemotherapy and similar-backbone HER2 therapy. Although we are not yet ready to embrace the concept of cytotoxic-free therapy for early HER2-positive disease in the clinic, the findings from this and other recently reported studies support conducting clinical trials with novel therapeutic approaches in primary HER2-positive breast cancer without chemotherapy and using pCR as a primary end point. Correlative science studies performed on tumor samples from these trials, including the TBCRC 006 study,6 will also provide valuable data to identify those patients who may not need chemotherapy.
FINALLY! results of NO CHEMO neoadjuvant trial of herceptin+tykerb+AI+/- LHRH agonist
Suzan W.
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