Trastuzumab: Qui Bono?

Extract

Beyond a doubt, trastuzumab works. In women with early-stage breast cancer, adjuvant use of the anti-HER2 monoclonal antibody trastuzumab reduces recurrence risk by half when added to standard chemotherapy (1). In fact, clinical experience suggests that data from randomized trials in the adjuvant setting may underestimate the real-world benefits. The success of trastuzumab for early-stage disease is so dramatic that many clinicians sense that the incidence of recurrence of HER2-positive breast cancer is plummeting, disappearing faster than the trials might have suggested.

But who really benefits from trastuzumab? It’s a question that might seem like asking, “Who’s buried in Grant’s tomb?” Since the first report more than 25 years ago that HER2 overexpression is an adverse prognostic factor in breast cancer (2), it has been an article of faith that the sine qua non for anti-HER2 treatments must be HER2 itself. Surely then, the importance of trastuzumab must have something to do with HER2. But in what ways, precisely? Does trastuzumab lower recurrence risk in all cases of HER2-overexpressing breast cancer across the board by 50%? Is there a subgroup of HER2-expressing tumors that are particularly sensitive to trastuzumab therapy? Is there a subgroup that is resistant? Based on experience with other novel, targeted agents, it seems unlikely that all patients derive similar benefit from trastuzumab. Meanwhile, a small but notable number of patients develop disease recurrence despite trastuzumab-based therapy. Paradoxically, although clinically “resistant,” such tumors still retain sensitivity to ongoing anti-HER2 treatment (3). A biomarker to identify those patients who are not likely to benefit from trastuzumab would be clinically useful, allowing patients to move in other therapeutic directions. Similarly, a marker that pegged tumors as exquisitely sensitive to anti-HER2 drugs might enable treatment without the blunt instrument of chemotherapy or define patients most suited for novel targeted or immunological approaches centering on HER2 expression. A predictive biomarker could be particularly important in the adjuvant setting where one cannot measure tumor response to assess the effectiveness of a therapy in an individual patient.