Adjuvant treatment of HER2-positive breast cancer: winning efforts continue to improve HER2-positive patient outcome long-term

Randomized adjuvant trials continue to show significant reductions in distant recurrence and death for early-stage women treated with adjuvant trastuzumab. BCIRG-006 showed superior disease-free and overall survival of two trastuzumab-containing regimens in comparison to a non-trastuzumab-containing regimen. The rates of disease-free and overall survival were not statistically different for the two trastuzumab-containing arms. Ongoing study is needed to identify markers of resistance to trastuzumab and incorporate newer agents in the adjuvant setting in order to further decrease rates of distant recurrence and death from HER2-positive breast cancer.


Abstract
Randomized adjuvant trials continue to show signifi cant reductions in distant recurrence and death for early-stage women treated with adjuvant trastuzumab. BCIRG-006 showed superior disease-free and overall survival of two trastuzumab-containing regimens in comparison to a non-trastuzumabcontaining regimen. The rates of disease-free and overall survival were not statistically diff erent for the two trastuzumab-containing arms. Ongoing study is needed to identify markers of resistance to trastuzumab and incorporate newer agents in the adjuvant setting in order to further decrease rates of distant recurrence and death from HER2-positive breast cancer. leukemias were seen in the two anthracycline-containing arms than in the TCH arm. Vomiting, arthralgias, myalgias, neuropathy, neutropenia and leukopenia were signifi cantly lower in the TCH group; anemia and thrombocytopenia were lower in the AC-TH group, and there was no signifi cant diff erence in febrile neutropenia between the arms.
Th ere were fewer distant recurrences of breast cancer in the AC-TH arm than the TCH arm (124 versus 144). Th ere were more congestive heart failure events in the AC-TH arm (21 versus 4), and one acute leukemia in both arms, for a total event rate of 146 for AC-TH versus 149 for TCH.
In summary, there are good reasons to administer either TCH or an anthracycline-containing regimen (AC-TH or AC-paclitaxel/traztuzumab) in the adjuvant setting after local therapy for HER2-positive early stage breast cancer. It is gratifying that both regimens have a 5 year OS rate above 90%, and that both regimens have a 5 year DFS rate of at least 73% in women with poor risk disease with four or more positive lymph nodes. Th e natural history of this aggressive subtype of breast cancer has indeed been changed. Which regimen chosen will likely depend on the comorbidity of the individual patient, and the desire to avoid cardiotoxicity.
Looking forward, no clear marker has materialized as a reliable predictor of traztuzumab resistance in the adjuvant setting. Newer agents are under active investigation and may improve outcomes for early-stage patients in combination with traztuzumab-based adjuvant therapy. Th ere also remains a lack of clarity regarding traztuzumab benefi t for HER2-negative and/or HER2-low patients. Finally, traztuzumab has yielded major advances in the treatment of an aggressive breast cancer phenotype, but oncologists remain divided regarding the relative riskbenefi t ratio of anthracyclines within traztuzumabcontaining adjuvant regimens [8,9].
Mechanisms of resistance to trastuzumab are complex and likely involve, in part, alternative signaling pathways and/or constitutive activation of the phosphoinositide 3-kinase/Akt signaling pathway. Newer agents show promise in resistant patients with advanced disease. Pertuzumab, a monoclonal antibody that binds to HER2 and inhibits heterodimeriza tion with other receptors of the Her superfamily, has shown progression-free survival benefi t in a phase III study in advanced disease [10] and is being studied in combination with trastuzumab with either anthracyline or non-anthracycline-based chemotherapy in the ongoing adjuvant APHINITY trial (NCT01358877). Trastuzumab-DM1, a con jugate of trastuzumab and a potent microtubule polymerization inhibitor (a derivate of maytansine) has shown a progression-free survival advantage in a phase II study of advanced disease [11]. Persistent HER3 signaling is another mechanism of therapeutic resistance, and anti-HER3 antibodies are in pre-clinical development. Combination studies of HER2-targeted agents with more potent, irreversible inhibitors of the epidermal growth factor receptor-HER2 family, such as Neratinib, are ongoing (NCT01423123). Retro spective analyses showing trastuzumab benefi t in HER2-negative patients [12] and a recent revised analysis of the N9831 trial showed similar DFS improvements with trastu zumab therapy in patients HER2-positive by US Food and Drug Administration criteria, but negative by the revised American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) criteria [13], making the ongoing pros pective NSABP trial (NCT01275677) looking at trastuzumab in HER2-low patients a priority to defi ne trastuzumab benefi t for those patients considered HER2low or -negative.
Despite improvements in treatment of advanced HER2-positive disease, many patients ultimately die due to progression of disease at visceral sites, so it is critical to increase success rates in the adjuvant setting.