Trastuzumab Has Radically Improved Prognosis for HER2+ Breast Cancer

Harold J. Burstein, MD, PhD, from the Dana-Farber Cancer Institute

Harold J. Burstein, MD, PhD

HER2-positive breast cancer has gone from "worst to first" because of the success of the monoclonal antibody drug trastuzumab (Herceptin) in combination with chemotherapy, said breast oncologist Harold Burstein, MD, of the Dana-Farber Cancer Institute, speaking Saturday in Chicago at the 19th Annual Lynn Sage Breast Cancer Symposium, sponsored by Northwestern University's Robert H. Lurie Comprehensive Cancer Center.

Disease-free survival rates have increased so dramatically since trastuzumab was introduced in 1998, and without significant toxicity from the drug, that, for a large proportion of patients, being diagnosed with this aggressive cancer is not the dire event it used to be.

About 1 in 5 of the 250,000 new breast cancers diagnosed every year is HER2 positive. About half are stage I and the remainder are stage II or III. Though HER2-positive cancers are more common in young women, they can occur at any age.

"Patients with stage I disease are doing very well with simple chemotherapy and trastuzumab and need nothing further," Burstein said. Patients with more advanced disease may get additional benefits from the use of 2 more recent agents, pertuzumab (Perjeta), approved for patients with HER2-positive metastatic breast cancer in 2012 and for neoadjuvant breast cancer treatment in 2013; and neratinib (Nerlynx), approved for extended adjuvant treatment of early stage HER2-positive breast cancer in July.

Burstein noted that more research needs to be done to determine where pertuzumab and neratinib are best incorporated into treatment regimens; currently, he recommends adding pertuzumab to trastuzumab for stage II or III disease, and adding neratinib at the beginning of year 2 for ER-positive tumors. He recommends caution in using neratinib because of significant side effects. The most common is diarrhea, which was severe in almost 40% of patients.¹

However, trastuzumab remains the starting point. A study of more than 4000 patients, published in 2014, showed that adding trastuzumab to chemotherapy led to a 37% relative improvement in overall survival, increasing 10-year survival from 75.2% to 84%. The 10-year disease-free survival rate increased from 62.2% to 73.7%. All patient subgroups benefited.²

The HERA trial found that a year of trastuzumab treatment is optimal.³A 2-year course did not improve disease-free survival and was associated with more side effects. However, the PHARE trial,⁴published in 2013, found that 6 months on trastuzumab was almost as beneficial and should be considered in areas of the world where adequate supplies of the drug are an issue, Burstein noted.

Studies also showed that trastuzumab is most effective when it is begun concurrent with chemotherapy rather than sequentially. Some studies suggest that chemotherapy will become less important as targeted therapies improve, Burstein said, though he doesn't anticipate being able to bypass chemotherapy altogether.

Burstein believes, based on his clinical experience, that trastuzumab works even better on HER2-positive tumors than published studies suggest, and that some of the patients studied may not actually have had HER2-positive disease.

"Our pathology has gotten much better and we can more reliably identify who really has HER2," he said, though he notes that accurate identification of HER2 is "the single most discussed" topic among Dana-Farber's tumor board. He expects that future studies with more precise pathology will bear out his clinical experience.

Burstein also suspects that trastuzumab may be somewhat overutilized because of "fear of missing out" when equivocal pathology results suggest HER2 positive disease but do not confirm it. "We have invested too little in gauging which tumors truly respond to treatment." He also called for greater investment in quality assurance in immunohistochemistry testing.

References

1. Chan A, Delaloge S, Holmes FA, et al. 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.http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00551-3/abstract. 2016;17:367-377.
2. Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for humanepidermal growth factor receptor 2—positive breastcancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831.JCO. www.scribd.com/doc/316400360/liposarkom. 2014;32:3744-3752.
3. Goldhirsch A, Gelber RD, Piccart-Gebhart M, et al. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial.Lancet Oncol. doi.org/10.1016/S0140-6736(13)61094-6. 2013;382(9897):1021-1028.
4. Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomized phase 3 trial.Lancet Oncol. www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70225-0/fulltext. 2013;14:741-748.