Charles Shapiro, MD
Icahn School of Medicine at Mount Sinai and Mount Sinai Health System, New York

Key Takeaways

  • The standard of care for patients with HER2-positive early breast cancer experiencing residual disease following neoadjuvant therapy is ado-trastuzumab emtansine (T-DM1) in the adjuvant setting, which is superior to trastuzumab in reducing the risk of recurrence.
  • Non-anthracycline regimens are noninferior to those containing an anthracycline and are a feasible option, especially for patients with a pre-existing cardiac condition or borderline ejection fraction at baseline.
  • Patients who achieve pathologic complete response after neoadjuvant therapy should continue with adjuvant trastuzumab, with or without pertuzumab, for a full year, because data supporting a shorter duration of treatment have been mixed.
  • There is an unmet need for new therapies to treat the approximately 25% of patients with HER2-positive early breast cancer who eventually experience relapse and develop brain metastasis.
  • Neoadjuvant therapy should be given to patients with stage II or III disease, whereas surgery is appropriate as an initial treatment for patients with smaller, node-negative tumors.

Charles Shapiro, MD, is a professor of medicine (hematology and medical oncology) at the Icahn School of Medicine at Mount Sinai in New York. He is director of Translational Breast Cancer Research for the Mount Sinai Health System and director of Survivorship Programs at The Tisch Cancer Institute. His clinical research interests include the impact of adjuvant chemotherapy on bone loss in premenopausal women, development of new treatments, and clinical trials that feature novel therapies.

HER2-positive breast cancer is a subtype that has seen a transformation of outcomes over the past 2 decades. What approaches are now used in this population that are considered the standard of care?

Development of HER2-directed therapies has led to advances in the treatment of HER2-positive disease, first in the adjuvant setting in the 2000s and then in the neoadjuvant setting in the 2010s. Adjuvant or neoadjuvant treatment, or both, with chemotherapy and trastuzumab is usually warranted in this setting, although other HER2-directed agents can also be used. Patients with stage II or III disease should receive neoadjuvant therapy, whereas surgery as initial treatment is appropriate for those with smaller, node-negative tumors.

The regimen varies depending on tumor size and node status. Treatment generally consists of chemotherapy with an anthracycline-based regimen containing cyclophosphamide given in a dose-dense fashion. If the patient is node positive, chemotherapy is given in combination with trastuzumab or pertuzumab. Chemotherapy plus trastuzumab is standard for all HER2-positive, node-positive breast cancers as well as for patients with larger node-negative tumors (>5 mm).

Non-anthracycline-based therapy consisting of docetaxel plus carboplatin plus trastuzumab, with or without pertuzumab is also an option for patients with stage II and III disease. But we tend to avoid anthracyclines in HER2/neu-overexpressing patients because of the risk of cardiotoxicity. Although this risk is small, with cardiac effects occurring in 1% or fewer of patients, anthracyclines do increase the risk of cardiomyopathy in this population.

Non-anthracycline-based therapy consisting of docetaxel plus carboplatin plus trastuzumab, with or without pertuzumab is also an option for patients with stage II and III disease. But we tend to avoid anthracyclines in HER2/neu-overexpressing patients because of the risk of cardiotoxicity.

Anthracyclines have been a mainstay of breast cancer therapy for decades because there has been strong evidence demonstrating their impact on breast cancer survival. As mentioned, there is a small but important increase in the risk of cardiotoxicity. Are non-anthracycline regimens as effective in the setting of early HER2-positive disease?

The Breast Cancer International Research Group 006 ( Identifier: NCT00021255) trial showed that non-anthracycline regimens were noninferior to those containing an anthracycline. More than 3000 women with HER2-positive, early-stage breast cancer were randomly assigned to receive 1 of 3 regimens studied: doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T); the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab); or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH).1

Estimated disease-free survival rates at 5 years were 75% in the AC-T group; 84% among patients receiving AC-T plus trastuzumab; and 81% among those receiving TCH. Estimated overall survival rates were 87%, 92%, and 91%, respectively.

The researchers found that adding 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival and that the risk:benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab. Efficacy was similar, and there were fewer acute toxic effects and lower risks of cardiotoxicity and leukemia.

HER2+ Treatment Strategies
Treatment for early-stage HER2-positive breast cancer can include some combination of surgery, targeted therapy, chemotherapy, and, possibly, other therapies.

What is the postsurgical treatment regimen for women who receive neoadjuvant therapy?

The choice of adjuvant treatment depends on their response to neoadjuvant treatment. Patients with residual disease will be switched to T-DM1 in the adjuvant setting, where it will be administered for 14 cycles. That is the new standard of care, which is superior to trastuzumab in lowering the risk of recurrence and prolonging disease-free survival.

Data for T-DM1 come from the KATHERINE trial ( Identifier: NCT01772472), which was an open-label, randomized study that included 1486 women with HER2-positive early breast cancer who had residual invasive disease after neoadjuvant taxane-containing chemotherapy (with or without anthracyclines) and trastuzumab. Patients were randomly assigned to receive adjuvant T-DM1 or trastuzumab for 14 cycles, and the primary endpoint was invasive disease-free survival.2 At 3 years, the rate of invasive disease-free survival was 88.3% in the T-DM1 group and 77.0% in the trastuzumab group (hazard ratio [HR] for invasive disease or death, 0.50 [95% CI, 0.39-0.64; P <.001]); distant recurrence as the first invasive disease event occurred in 10.5% of patients in the T-DM1 group compared with 15.9% in the trastuzumab group.

If there is no residual disease and the patient has achieved pathologic complete response, adjuvant trastuzumab will be given, with or without pertuzumab, for 1 year. A newer therapy, neratinib, was approved in 2017 for extended adjuvant therapy for early-stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy. This approval was based on the phase 3 ExteNET trial ( Identifier: NCT00878709), which showed improvement, after 2 years of follow-up, in invasive disease-free survival (93.9% in the neratinib group compared with 91.6% in the placebo group).3 Neratinib is generally given to women at higher risk for recurrence. To date, there are no data showing a benefit in women who have received pertuzumab or T-DM1 as part of their neoadjuvant treatment.

Do all women receive trastuzumab for a year, regardless of their response to adjuvant treatment?

There has been some interest in de-escalating trastuzumab. A few trials have looked at decreasing follow-up treatment to 6 months, but results failed to reach a firm conclusion. The PHARE trial ( Identifier: NCT00381901) failed to show that 6 months of adjuvant trastuzumab therapy was noninferior to 12 months in patients after 7 months of follow-up. At 3 years, the rate of disease-free survival was 92.2% with 12 months of trastuzumab compared with 89.3% with 6 months of therapy. At 5 years, these rates were 86.2% and 84.2%, respectively, and at 7 years were 82.3% and 80.6%, respectively, favoring the longer course of treatment.4

However, the PERSEPHONE trial ( Identifier: NCT00712140) did show noninferiority of 12 months compared with 6 months of trastuzumab, albeit with shorter follow-up.5 The 4-year disease-free survival was 89.4% in the 6-month group and 89.8% in the 12-month group (HR for noninferiority of 6-month treatment, 1.07 [90% CI, 0.93-1.24; P =.011]).
Studies have also looked for any benefit to extending trastuzumab beyond 1 year. The HERA trial ( Identifier: NCT00045032), which randomly assigned more than 5000 women to observation or to the addition of trastuzumab for 1 or 2 years following completion of chemotherapy, found no difference in 10-year disease-free survival between 1 or 2 years of trastuzumab. The study reported survival to be 69% in both arms (HR, 1.02 [95% CI, 0.89-1.17]).6 Treatment with trastuzumab was superior to the 63% disease-free survival rate in the observation group, however.

Before the advent of HER2‐targeted therapy, this subtype was associated with aggressive disease, with a high recurrence rate and poorer survival outcomes. Newer therapies have changed the paradigm of HER2-positive breast cancer, but patients still experience relapse. What unmet needs do you see in this population?

Approximately 15% to 25% of patients treated with HER2-directed therapy experience disease relapse. Although relapse can occur in any part of the body, brain metastasis is really the unmet need. Approximately 25% of patients eventually develop brain metastases, which have been difficult to treat. Basically, the brain is a sanctuary, and current treatments are unsuccessful in that region. Trastuzumab, for example, can reach preclinical brain tumors, but it is not as effective at controlling intracranial disease in the clinical setting. This is reminiscent of, and parallels, what we saw early on in pediatric acute lymphoblastic leukemia, in that many recurrences were not in the body but in the brain. Patients with acute lymphoblastic leukemia now receive extensive CNS-directed chemotherapy — regimens that target systemic disease and these sanctuary sites.

In the HER2CLIMB study ( Identifier: NCT02614794), patients with either metastatic or nonoperable HER2-positive breast cancer who received the tyrosine kinase inhibitor tucatinib in combination with capecitabine and trastuzumab showed statistically significant improvement in progression-free survival.7 Secondary analysis of the HER2CLIMB trial data that focused on the 48% of patients with brain metastasis showed a 68% reduction in the risk of intracranial progression and death in this subset.8 Median CNS progression-free survival was 9.9 months in the tucatinib arm compared with 4.2 months for controls. Median overall survival was 18.1 months for tucatinib compared with 12.0 months for controls. Overall response rate was also higher in the tucatinib arm at 47.3% (95% CI, 33.7-61.2) compared with the control arm at 20.0% (95% CI, 5.7-43.7; P =.03). Based on these findings, tucatinib in combination with trastuzumab and capecitabine received regulatory approval for use in this setting.9

The variables for developing brain metastases are still unclear, and there are newer drugs being tested in clinical trials. For now, this is the regimen approved by the US Food and Drug Administration for this population.

The Q&A was edited for clarity and length.


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  2. von Minckwitz G, Huang CS, Mano MS et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628. doi:10.1056/NEJMoa1814017
  3. Chan A, Delaloge S, Holmes FA et al; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17(3):367-377. doi:10.1016/S1470-2045(15)00551-3
  4. Pivot X, Romieu G, Debled M, et al; PHARE Trial Investigators. 6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicentre, open-label, phase 3 randomised trial. Lancet. 2019;393(10191):2591-2598. doi:10.1016/S0140-6736(19)30653-1
  5. Earl HM, Hiller L, Vallier A-L, et al; PERSEPHONE Steering Committee and Trial Investigators. 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial. Lancet. 2019;393(10191):2599-2612. doi:10.1016/S0140-6736(19)30650-6
  6. Cameron D, Piccart-Gebhart MJ, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017;389(10075):1195-1205. doi:10.1016/S0140-6736(16)32616-2
  7. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609  
  8. Lin NU, Borges V, Anders C, et al. Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB Trial. J Clin Oncol. 2020;38(23):2610-2619. doi:10.1200/JCO.20.00775
  9. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer.  Press release. US Food and Drug Administration. April 20, 2020. Accessed March 20, 2021.

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Reviewed March 2021