About 1 in 5 women diagnosed with breast cancer will have HER2-positive disease, an aggressive breast cancer subtype.1 In recent years, the development of HER2-targeted therapies such as pertuzumab and trastuzumab have significantly improved the natural history of HER2-positive breast cancer.

Most women diagnosed with early-stage invasive, HER2-positive breast cancer will undergo surgery to remove the tumor.3 Those women with larger or more aggressive HER2-positive cancers may undergo neoadjuvant treatment with chemotherapy plus trastuzumab in order to shrink the tumor prior to surgery.

A subset of women who undergo neoadjuvant treatment and surgery will achieve a pathologic complete response, with no residual invasive disease in the breast or axillary lymph nodes. For women with HER2-positive disease, between 30% to 70% of women may achieve pathologic complete response, depending on hormone receptor status.4

However, presence of residual disease after surgery indicates a partial resistance in the tumor and adjuvant treatment is required.

Residual Disease Options

For patients with residual disease after preoperative treatment, the National Comprehensive Cancer Network (NCCN) recommends ado-trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine (Table 1).5 Originally approved in metastatic breast cancer, T-DM1 received expanded U.S. Food and Drug Administration approval for certain women with early-stage, HER2-positive breast cancer in May 2019.6

To be eligible for the drug, women must have first undergone neoadjuvant therapy to shrink the tumor and still have signs of residual disease in the breast or nearby lymph nodes.

T-DM1 was approved in early-stage disease based on the results of the KATHERINE trial (ClinicalTrials.gov Identifier: NCT01772472).7 The phase 3 trial included 1486 women with HER2-positive, early-stage breast cancer and residual invasive disease who were randomly assigned to receive either T-DM1 or trastuzumab.

After treatment, risk of residual invasive disease was 50% lower for women assigned to receive T-DM1 compared with trastuzumab alone (hazard ratio [HR], 0.50; 95% CI, 0.39-0.64; P <.001). At 3 years, 88.3% of patients assigned to receive T-DM1 were free of invasive disease compared with 77.0% of patients assigned to receive trastuzumab. Additionally, distant recurrence was the first invasive disease in 10.5% of women who received T-DM1 compared with 15.9% of women receiving trastuzumab.

T-DM1 was administered at a dose of 3.6 mg/kg of body weight every 3 weeks for 14 cycles and 71.4% of patients completed all 14 cycles.7

Serious adverse events occurred in 12.7% of patients assigned to receive T-DM1 and 8.1% of patients assigned to receive trastuzumab. Adverse events leading to drug discontinuation occurred in 18% of patients assigned to receive T-DM1 compared with 2.1% of patients assigned to receive trastuzumab. The most common adverse events leading to discontinuation of T-DM1 were decreased platelet count, elevated blood bilirubin level, elevated aspartate aminotransferase level and elevated alanine aminotransferase level, peripheral sensory neuropathy, and decrease ejection fraction.7

The T-DM1 package insert warns that hepatotoxicity, liver failure, and death have occurred in patients treated with the drug. Clinicians should monitor hepatic function prior to initiation and prior to each dose, and should institute dose modification or discontinue use as appropriate. Additionally, clinicians are advised to assess left ventricular ejection fraction prior to initiation.8

No Residual Disease Options

If there is no residual disease after preoperative therapy, the NCCN guidelines recommend completion of up to 1 year of HER2-targeted therapy with trastuzumab with or without pertuzumab.5

A 2012 meta-analysis confirmed the benefit of adjuvant trastuzumab in patients with HER2-positive disease.9 The analysis included data from 8 studies including almost 12,000 patients and concluded that trastuzumab significantly improved overall survival (HR, 0.066; 95% CI, 0.57-0.77; P <.00001) and disease-free survival (HR, 0.60; 95% CI, 0.50-0.71; P <.00001). However trastuzumab was also associated with significantly increased risk for congestive heart failure (risk ratio [RR], 5.11; P <.00001) and left ventricular ejection fraction decline (RR, 1.83; P =.0008).

More recently, data from a combined overall survival analysis of the NSABP B-31 (ClinicalTrials.gov Identifier: NCT00004067) and NCCTG N9831 (ClinicalTrials.gov Identifier: NCT00005970) trials found that trastuzumab in combination with adjuvant chemotherapy resulted in a 37% relative improvement in overall survival and a 40% improvement in disease-free survival.10

The prescribing information for trastuzumab calls for administration of the drug at an initial dose of 4 mg/kg over a 90-minute infusion, then 2 mg/kg over a 30-minute intravenous infusion weekly for 52 weeks or an initial dose of 8 mg/kg over 90 minute infusion, then 6 mg/kg over a 30- to 90-minute infusion every 3 weeks for 52 weeks. Treatment is typically started 4 to 6 weeks after surgery (Table 2).11

The label also warns of cardiomyopathy, infusion reactions, and pulmonary toxicity, and advises the use of contraception for women of reproductive potential during treatment and for 7 months after.11

Adjuvant dual anti-HER2 therapy combining trastuzumab with pertuzumab is another option for patients who achieved pathological complete response after neoadjuvant treatment and are considered to be high risk.

The phase 3 APHINITY trial (ClinicalTrials.gov Identifier: NCT01358877) demonstrated that pertuzumab improved invasive disease–free survival in patients with HER2-positive, operable breast cancer when added to trastuzumab and chemotherapy.12 The 3-year estimated invasive disease–free survival was 94.1% for patients assigned to the pertuzumab combination group compared with 93.2% for patients in the placebo group. 

Cardiac toxicities such as heart failure, cardiac death, and cardiac dysfunction were infrequent in this study. However, grade 3 or worse diarrhea occurred during chemotherapy and was more frequent with pertuzumab compared with placebo (9.8% vs 3.7%, respectively).

Pertuzumab is given at an initial dose of 840 mg administered as a 60 minute intravenous infusion followed every 3 weeks thereafter by 420 mg administered as a 30 to 60 minute infusion (Table 2).13

For women with HER2-positive, hormone receptor–positive disease, extended adjuvant neratinib may also be given after adjuvant trastuzumab-containing therapy.5 Neratinib is a HER2-directed tyrosine kinase inhibitor.

A phase 3 trial (ClinicalTrials.gov Identifier: NCT00878709) of 2840 women with early-stage, HER2-positive breast cancer found that women randomly assigned to receive neratinib had an improved 5-year invasive disease–free survival compared with those who did not receive neratinib (HR, 0.73; 95% CI, 0.57-0.92; P =.0083).14 There was a trend toward improved disease-free survival for women with hormone receptor–positive disease (HR, 0.60; 95% CI, 0.43-0.83). In contrast, no trend was seen for women with hormone receptor–negative disease (HR, 0.95; 95% CI, 0.66-1.35).

Neratinib is administered as 240 mg orally once daily with food for 1 year. In clinical trials, common grade 3 to 4 adverse events for neratinib were diarrhea, vomiting, and nausea.14

Prescribing information for neratinib advises use of antidiarrheal prophylaxis with the first dose of the drug continuing during the first 2 cycles of treatment. Diarrhea occurring despite prophylaxis should be aggressively managed with antidiarrheals, fluids, and electrolytes. Additionally, clinicians should monitor for hepatotoxicity for the first 3 months of treatment and then every 3 months thereafter (Table 2).15

References

  1. Targeted Therapy for Breast Cancer. American Cancer Society website. www.cancer.org/cancer/breast-cancer/treatment/targeted-therapy-for-breast-cancer.html. Published June 29, 2020. Accessed September 9, 2020.
  2. Cancer Stat Facts: Female Breast Cancer Subtypes. National Cancer Institute Surveillance, Epidemiology, and End Results Program website. seer.cancer.gov/statfacts/html/breast-subtypes.html. Accessed September 29, 2020.
  3. Breast Cancer: Types of Treatment. Cancer.Net website. www.cancer.net/cancer-types/breast-cancer/types-treatment. Approved July 2020. Accessed September 11, 2020.
  4. Caparica R, Lambertini M, Ponde N, et al. Post-neoadjuvant treatment in the management of residual disease in breast cancer: state of the art and perspectives. Ther Adv Med Oncol. 2019;11:1758835919827714. doi:10.1177/1758835919827714
  5. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Breast Cancer NCCN Evidence Blocks (Version 5.2020).  NCCN website. www.nccn.org/professionals/physician_gls/pdf/breast_blocks.pdf. Updated July 15, 2020. Accessed September 9, 2020.
  6. FDA approves ado-trastuzumab emtansine for early breast cancer. U.S. Food & Drug Administration website. www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-adotrastuzumab-emtansine-early-breast-cancer. Accessed September 11, 2020.
  7. Von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2020;380:617-628. doi:10.1056/NEJMoa1814017
  8. Kadcyla (ado-trastuzumab emtansine). Prescribing Information. Genentech; May 2019. Accessed September 11, 2020. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125427lbl.pdf
  9. Moja L, Tagliabue L, Balduzzi S, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012(4);CD006243. doi:10.1002/14651858.CD006243.pub2
  10. Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 204;32(33):3744-3752. doi:10.1200/JCO.2014.55.5730
  11. Herceptin (trastuzumab). Prescribing Information. Genentech; October 2010. Accessed September 11, 2020. www.accessdata.fda.gov/drugsatfda_docs/label/2010/103792s5250lbl.pdf.
  12. Von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2):122-131. doi:10.1056/NEJMoa1703643
  13. Perjeta (pertuzumab). Prescribing Information. Genentech; 2012. Accessed September 11, 2020. http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125409lbl.pdf  
  14. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(12):1688-1700. doi:10.1016/S1470-2045(17)30717-9
  15. Nerlynx (neratinib). Prescribing Information. Puma Biotechnology, Inc.; July 2017. Accessed September 11, 2020. www.accessdata.fda.gov/drugsatfda_docs/label/2017/208051s000lbl.pdf

Reviewed September 2020