Drs. Jelovac and Emens have conducted a comprehensive review of human epidermal growth factor receptor 2 (HER2)-targeted treatment for metastatic breast cancer. They have carefully reviewed the three available classes of agents—monoclonal antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates—and shown that each has contributed to improved treatment of this disease.
Prior to the advent of HER2-directed therapies, breast cancers with amplification of the HER2 gene were associated with significantly shorter disease-free survival vs tumors without amplification.[1] Since the approval of trastuzumab(Drug information on trastuzumab) (Herceptin) in 1998 as the first HER2-directed therapy, the field has continued to develop rapidly. In the pivotal trial in the first-line metastatic setting, addition of trastuzumab to chemotherapy increased the median overall survival (OS) from 20 months to 25 months (P = .046), despite a 72% crossover rate.[2] With the recent approval in 2012 of pertuzumab (Perjeta) in combination with trastuzumab and docetaxel(Drug information on docetaxel) in the first-line setting, the median OS is expected to be substantially longer.[3] In the most recent update of the CLEOPATRA trial, with a median follow-up of 30 months, the median OS of patients on the three-drug combination had not yet been reached, as compared with 37.6 months OS for patients who received trastuzumab and docetaxel.[4] Risk of death was reduced by 34% for people who received pertuzumab in addition to trastuzumab plus docetaxel (HR = 0.66; P = .0008). Despite these groundbreaking advances, some unanswered questions remain.
Central nervous system (CNS) disease has become a challenging and devastating cause of morbidity and mortality in HER2-positive metastatic breast cancer. This is thought to be due, in part, to an inherent affinity of HER2-positive tumors for the CNS.[5] In addition, the success of HER2-directed therapy has also likely led to the increased incidence of brain metastases in these patients. Typically, brain metastases present late in the disease course. Since the advent of these therapies, which often provide excellent, long-term systemic control of metastatic disease, patients are surviving long enough to develop brain metastases and suffer from their consequences. Local treatment options, including surgery, whole brain radiation therapy (WBRT), and stereotactic radiosurgery remain the standard of care for CNS metastases. Systemic treatment options are limited. Trastuzumab does not cross the blood-brain barrier (BBB) due to its large size (185 kDa), thus improved systemic control and prolonged survival with poor CNS protection allow for the development of brain metastases. Lapatinib (Tykerb) appears to be the most promising treatment for CNS metastases, due to its small size (581 Da) and ability to cross the BBB. As the authors mentioned, recent results from the LANDSCAPE trial showed that the combination of lapatinib plus capecitabine(Drug information on capecitabine) yielded a high CNS response rate of 67% among 43 evaluable patients, with a median time to progression of 5.5 months and a median time to WBRT of 8.3 months.[6] Trials are ongoing with neratinib (HKI-272) and afatinib (BIBW 2992), other small molecules that may cross the BBB. This is clearly an area in which research needs to be focused, in terms of treatment and prevention.
The authors have also correctly concluded that dual targeting of HER2, by whichever means, produces a better outcome than single targeting, and that targeting the HER2 receptor and the estrogen receptor (ER) is superior to targeting either one alone. As newer agents emerge, their combinations with the current ones (trastuzumab, lapatinib, and pertuzumab)will need to be established. One arena in which to explore these combinations is the neoadjuvant setting. Significant pathologic complete response (pCR) rates have been seen for dual anti-HER2 therapies without chemotherapy. In NeoSphere, a randomized, open-label, phase II trial, 417 patients with locally advanced, inflammatory, or early HER2-positive breast cancer were randomized to treatment with trastuzumab plus docetaxel; pertuzumab plus trastuzumab plus docetaxel; pertuzumab plus trastuzumab; or pertuzumab plus docetaxel.[7] The highest pCR rate (45.7%) was seen in the patients who received both antibodies plus docetaxel, but importantly, a pCR rate of 16.8% was seen in the patients who received pertuzumab plus trastuzumab without chemotherapy. This naturally leads one to ask whether triple or quadruple targeting will produce even better results. These challenges will likely only be met through cooperative group studies, supported by the federal government, because these molecular agents are often owned by different companies with competing mandates.
HER2 is similar to ER in that direct targeting of either receptor with a single drug can lead to safe, durable remission with excellent quality of life, as seen with use of trastuzumab for HER2+ disease or tamoxifen(Drug information on tamoxifen) for ER+ disease. Yet the single, sequential-agent approach used in treating ER+, HER2-negative breast cancer, and which is considered to be the standard of care, has not been adopted in HER2-positive breast cancer. Instead, chemotherapy plus HER2-targeted treatment (and now chemotherapy plus dual HER2-targeted treatment, as used in the CLEOPATRA trial) has been approved by the US Food and Drug Administration as front-line therapy.
Is such aggressive treatment necessary for all patients? Are there some patients who could begin treatment with trastuzumab and, upon progression, receive treatment with additional agents, achieving similar survival and better quality of life, but at a lower cost? This hypothesis has not been tested in HER2-positive breast cancer because the original trastuzumab trials required that it be added to what was then considered standard of care, that is, chemotherapy. What if there had been a third arm, trastuzumab alone, in the pivotal trial by Slamon et al[2]? Concurrently with the pivotal trial, there was a phase II trial in which single-agent trastuzumab was given as front-line treatment.[8] While cross-trial comparisons are difficult, it is interesting to note that the progression-free survival curves from this trial were virtually identical to the chemotherapy-plus-trastuzumab curve in Slamon’s trial. The forest plot from CLEOPATRA supports the idea that some patients, that is, those with nonvisceral disease, may do just as well with two drugs instead of three.[3]
Developing biomarkers that predict sensitivity to a given targeted therapy would be ideal. However, despite much research in this area, the only robust biomarker of response to HER2-targeted therapies is HER2 itself. While we await the ideal predictive test, clinical trials that begin with a single agent and layer on additional treatments at disease progression would help to distinguish patients who have tumors that are addicted to HER2 signaling alone from those with more complex biology. Such trials should be conducted in parallel with the search for biomarkers.
The game changer in this debate may well be trastuzumab emtansine (T-DM1 [Kadcyla]). This drug is trastuzumab plus chemotherapy, without the alopecia, neutropenia, nausea, or vomiting. To this end, results of the MARIANNE trial (a phase III, randomized study of T-DM1 with or without pertuzumab vs trastuzumab plus taxane for first-line treatment of HER2-positive, progressive, or recurrent locally advanced or metastatic breast cancer) are eagerly awaited.
As more drugs become available in the HER2 arena, clinicians will be faced with increasing challenges regarding which sequences and combinations of drugs will be the best for their patients. In the era in which we practice, a great deal of this is likely to be dictated by the payers. When trastuzumab was first available as the only HER2-directed therapy, the practice to continue it through multiple lines of treatment became standard. The evidence to support this continued use came only later.[9-11] It is questionable whether clinicians will be able to have the same freedom with use of these newer agents, prior to availability of the supporting evidence.
The recently approved agents and those that are about to be approved are a welcome addition to our doctor bag. We look forward to learning more about them, including their long-term tolerability. We now know that patients with HER2-positive metastatic breast cancer can live a long time, some over a decade. Whether newer treatments will be as forgiving as good old trastuzumab remains to be seen.
Financial Disclosure: Dr. Cobleigh serves on the advisory board of, and receives research funding from, Genentech/Roche, and is on the data safety and monitoring committee of GlaxoSmithKline. Dr. Rao is a consultant to, and serves on the advisory board of, Genentech.
