HER2-positive breast cancer accounts for approximately 20% of all breast invasive tumors. The identification of this receptor in the late 1980s has dramatically improved the treatment of breast cancer and has tremendously improved the prognosis of patients with HER2 amplification/overexpression. In breast cancer, HER2 is a well-established predictive biomarker of benefit from HER2-directed therapies, the most widely used being trastuzumab.
In the adjuvant setting, trastuzumab meaningfully improved outcomes of patients with HER2-positive disease . One of the pivotal studies testing the efficacy and safety of adjuvant trastuzumab was the HERA trial . In this multinational, open-label phase III trial, 5102 women with HER2-positive early breast cancer were randomized to one of 3 treatment arms: chemotherapy alone, chemotherapy followed by trastuzumab for 1 year and chemotherapy followed by trastuzumab for 2 years. In the recently published long-term follow-up analysis, after 11 years of median follow-up, 79% of patients who received 1-year trastuzumab were alive (HR 0.74, 95% CI 0.64-0.86; absolute 6.5% improvement compared to no trastuzumab) and 69% free of recurrence or death (HR 0.76, 95% CI 0.68-0.86; absolute 6.8% improvement compared to no trastuzumab). This benefit was observed in patients with both hormone receptor-positive and negative disease. No new safety signals were reported after this long follow-up. Adverse events of special interest in patients receiving trastuzumab include cardiac toxicity, with the most common one being asymptomatic decrease in left ventricular ejection fraction (LVEF). After 11 years of follow-up, serious cardiac events (defined as New York Heart Association [NYHA] class III-IV heart failure, cardiac death or decline of LVEF ≥ 10% to below 50%) were rare: 1% for both trastuzumab arms as compared to 0.1% for chemotherapy alone arm. On the other hand, less severe cardiac events (NYHA I-II heart failure or decrease in LVEF ≥ 10% to a value below 50%) were more common in the 2-year trastuzumab arm (7.3%) than in the 1-year trastuzumab arm (4.4%) or chemotherapy alone arm (0.9%). It is however noteworthy that the rates of cardiac events during second year of adjuvant trastuzumab were similar to those during the first year of treatment and rates fell in a similar pattern after trastuzumab completion in both the 1- and 2-year arms. Also, it is well known that most of these cardiac events do occur during treatment phase and that the vast majority of those do recover when the drug is stopped and proper cardiac co-medications are given.
Of note, despite the sound efficacy results with the use of the current standard of care in patients with HER2-positive early breast cancer (i.e. chemotherapy and adjuvant trastuzumab for 1 year), approximately 30% of patients still developed a disease event, of which around 18% as distant relapse. Conversely, 63% of patients were cured with chemotherapy alone. Hence, these results highlight the heterogeneity of the HER2 population and the need for treatment escalation strategies in some patients and treatment de-escalation strategies in others .
In this setting, the HERA trial was innovative in testing the role of treatment escalation with the prolongation of adjuvant trastuzumab for two years. To this end, despite the early separation of curves after 1 year of treatment, such trend was not consistent over time, culminating in an overlapping effect between 1 and 2 years of this agent. Beyond prolonging adjuvant trastuzumab, other studies sought alternative strategies of treatment escalation. The ALTTO trial tested the addition of lapatinib, an orally reversible tyrosine kinase inhibitor (TKI) of HER1 and HER2, to 1 year of adjuvant trastuzumab without statistical nor clinical relevant improvement in disease outcomes . The ExteNET trial showed a statistically significant but clinical marginal improvement in outcomes from sequential use of neratinib, an oral irreversible TKI of HER1, HER2, and HER4, after 1 year of adjuvant trastuzumab at the cost of added toxicity (the most important being diarrhea grade 3/4 in approximately 40% of patients) . Similarly, the APHINITY trial testing the role of another anti-HER2 dual blockade strategy with concurrent administration of pertuzumab and trastuzumab for 1 year showed statistical significant but only marginal improved outcomes . Three-year invasive disease-free survival (iDFS) was 94.1% in the pertuzumab group and 93.2% in the placebo group (HR 0.81, 95% CI 0.66-1.00). The benefit of adding pertuzumab seemed to be slightly better in patients with node-positive disease and hormone receptor-negative disease (absolute 3 years iDFS difference of 1.8% and 1.6%, respectively). All these data highlight that despite the best chemotherapy and anti-HER2 strategy available today, some patients will experience disease recurrence. Hence, other strategies of treatment escalation should focus on better patient selection, based on other tumor features beyond HER2 expression (e.g. biomarkers) or based on a better estimation of recurrence risk (e.g. escalation of treatment in patients with residual disease after neoadjuvant therapy as currently investigated in the KATHERINE trial [NCT01772472]). In this context, there might be room for immune directed interventions in addition to trastuzumab in order to enhance its immune specific action. These strategies could be of special interest for hormone receptor-negative patients that will not receive further treatments after completing adjuvant trastuzumab.
Conversely, there is definitely room for strategies aiming at treatment de-escalation because not all patients require all drugs available in our oncologic armamentarium. Reducing the time of adjuvant trastuzumab administration failed in demonstrating the non-inferiority of shorter duration of anti-HER2 treatment as compared to the 1-year standard . However, the most important de-escalation strategies so far focused on reducing the burden of adjuvant chemotherapy. Recent data demonstrated that it is feasible and safe to remove the anthracycline component of companion adjuvant chemotherapy in specific subgroups of patients. In the APT trial, patients with node-negative disease and tumors smaller than 3 cm received weekly paclitaxel and trastuzumab for 12 weeks, followed by 9 months of trastuzumab monotherapy with excellent survival outcomes . The BCIRG006 trial showed that a non-anthracycline-containing regimen with docetaxel and carboplatin (i.e. TCH) given every 3 weeks for 6 cycles and trastuzumab for 1 year is associated with acceptable survival outcomes with fewer cardiac events as compared to anthracycline-based chemotherapy plus 1-year trastuzumab. Finally, Jones and colleagues also showed that 4 cycles of TC regimen (i.e. docetaxel and cyclophosphamide) plus trastuzumab for 1 year had good disease outcomes results in patients with tumors that were node-negative and smaller than 2 cm in the majority of the cases . In trying to radically change the way adjuvant chemotherapy is administered to HER2-positive patients, the ATEMPT trial (NCT01853748) is currently studying the role of adjuvant single agent TDM-1 for patients with stage I disease.
Taken together, the impressive body of knowledge built so far supports that 1 year of trastuzumab remains standard of care for patients with early-stage HER2-positive breast cancer. However, room for treatment improvement exists. Looking ahead, and despite the improvements that patients with HER2-positive disease have benefited from, we should focus our efforts in defining to whom we should seek treatment escalation and, conversely, to whom we should recommend and seek treatment de-escalation. And these points go hand in hand with finding predictors of response beyond HER2 positivity, at least in the form as we measure it nowadays. Finally, access to trastuzumab in Europe is still heterogeneous and efforts to ensure that indisputably effective and safe drugs move to clinical practice are in great need . These are some of the issues that all young oncologists aiming at advancing the field of HER2-positive early breast cancer should bear in mind.
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What strategies would you suggest to address treatment de-escalation and escalation in HER2-positive early breast cancer?
Arlindo R. Ferreira and Matteo Lambertini declare no actual, potential, real or apparent interest. The authors declare to have no involvement that might raise the question of bias in the work reported or in the conclusions, implications, or opinions stated.