Where to With HER2

Last week in clinic, I was trying to explain HER2 and its effect on prognosis to a patient with newly diagnosed breast cancer. “It’s HER2 positive,” she said, “That’s bad, right?” Well, no, I explained, it used to be awful, but now it’s much better, and it’s going to get better yet in the not-too-distant future. Later in the same clinic, I saw a patient who had received therapy for HER2+ disease metastatic to the liver for a total of 7 years. Anecdotes are dangerous, particularly anecdotes involving success stories: the dead are not present to comment on our failures. But I suspect these anecdotes could be repeated in many an oncologist’s clinic and were almost unimaginable little more than a decade ago. The evolution of the HER2 story continues to delight and encourage, both for how far we’ve come and for what it means about breast cancer as a whole. And how far we’ve come: from the identification of HER2+ breast cancer as a distinct biologic subset with an aggressive natural history, to a successful target in the metastatic setting, to the adjuvant success seen in that annus mirabilis of 2005, to a continuing target as we learn more about resistance and the means by which it might be defeated once and for all. Currently, there are 2 approved agents specific to the treatment of patients with HER2+ disease: the monoclonal antibody trastuzumab and the small-molecule receptor tyrosine kinase inhibitor lapatinib. Clearly, other agents are on the way, and some should be standard tools in the near future. These include agents inhibiting receptor dimerization, agents using HER2-targeted antibodies as delivery vehicles for cellular poisons, other small-molecule inhibitors of the HER family, inhibitors of downstream pathway components (PI3K and mTOR), inhibitors affecting degradation of the HER2 molecule, and inhibitors of receptors that have significant interactions with HER2 (eg, VEGFR and IGF-1R). Several of these are under active investigation, several already are demonstrating exciting levels of activity, and several are likely to find their way into routine clinical practice. Greedy clinical investigators (I count myself among them) have more new drugs than patients in the HER2 investigational space. The explosion of new drugs, and the availability of new data, leaves many unanswered questions in the adjuvant and metastatic settings. Is there a “best” chemotherapy combination in the adjuvant setting (a question that has generated as much heat as light)? Is adjuvant trastuzumab best given with or following adjuvant chemotherapy? How long should HER2-targeted therapy be administered in either the adjuvant or metastatic setting (a long time, if the metastatic data are to be believed; a short time, if early adjuvant data are correct)? Are there patients with HER2+ disease who may be treated entirely without chemotherapy? How low should one go (size-wise) in the adjuvant setting in using HER2-targeted therapy? What exactly constitutes a patient with HER2+ disease in the adjuvant setting? As new agents targeting HER2 come forward, how should they be combined (other than the serendipitous development of 2 agents by the same company)? Many other questions might join this list, I suspect. Answering these questions has become something of a problem for clinical investigators. There are (thankfully) fewer patients with HER2+ metastatic disease than there were 5 years ago and more agents and logarithmically more combinations and questions to be tested. In the adjuvant setting, the success of the initial wave of studies means that new studies must involve larger numbers of patients followed for longer periods of time. Already, adjuvant trials must be multicontinental to answer simple questions in a timely fashion; in the near future, HER2+ disease might become prohibitively expensive to study, in terms of both financial and patient resources. I began this editorial by saying that “the evolution of the HER2 story continues to delight and encourage, both for how far we’ve come and for what it means about breast cancer as a whole.” What it means for breast cancer as a whole is something more profound. Our success in the HER2 arena has many reasons, but the simplest can be stated as follows: (1) identify crucial biology, (2) measure that biology in the clinic, (3) target that biology, (4) identify mechanisms of resistance, and (5) iteratively target resistance mechanisms. It’s not always this easy, you might say, and HER2 may have been lowhanging fruit. But the approach should be repeatable, until breast cancer gets ever less frightening—a historical curiosity rather than an ongoing nightmare.