To escalate or de-escalate? The question in HER2-positive breast cancer (1)

The topic was debated on Saturday in a session as part of the Young Oncologist Track, highlighting the pros and cons of the two different approaches currently in use. There is no question that the clinical benefit and safety profile of the trastuzumab-chemotherapy combination is undeniable in both metastatic and early-stage settings. Several trials have shown benefits for escalating treatment with dual anti-HER2 blockade, driven by the need for more intense treatment in those patients at high risk of disease relapse.In my experience of dual HER2 blockade-chemotherapy regimens, the chemotherapy component has the most detrimental impact on patient well-being and once chemotherapy is stopped and anti-HER2 therapies are given alone, quality of life returns to acceptable levels. High costs and the identification of patients who really require dual anti-HER2 blockade are further limitations of escalated therapy.In early-stage disease, the NeoSphere trial showed that further treatment escalation combining taxane chemotherapy with the complementary anti-HER2 monoclonal antibodies, trastuzumab and pertuzumab, improved efficacy outcomes (pathological complete response, pCR). In the metastatic setting, trastuzumab–pertuzumab–taxane chemotherapy prolonged median overall survival by a remarkable 16 months compared with trastuzumab–chemotherapy in the CLEOPATRA trial. Even in those with early-stage, node-positive disease—a high-risk patient population—patients derive a significant benefit from adjuvant pertuzumab–trastuzumab–chemotherapy treatment, as shown in the APHINITY trial. Consequently, dual anti-HER2 blockade is approved for the adjuvant treatment of high-risk patients.In patients with residual disease after neoadjuvant therapy (including anti-HER2 treatment), treatment change with adjuvant trastuzumab–emtansine (T-DM1) in the KATHERINE trial also improved invasive disease-free survival compared with maintaining trastuzumab therapy, which led to US FDA approval of this regimen in this setting.Adjuvant dual anti-HER2 blockade is generally approved for high-risk patients, which are defined differently across countries. I think that using node positivity as a defining feature of high-risk disease is a pragmatic way of filtering treatment to those most likely to benefit, whilst simultaneously controlling costs of unnecessary therapy in the entire population.

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