Stage, ER Status Guide HER2 Therapy Selection in Breast Cancer

Harold J. Burstein, MD, PhD

There are now several agents approved for the treatment of patients with HER2-positive breast cancer, placing the focus on the sequencing of therapies, which is largely driven by stage of disease and hormone receptor status, said Harold Burstein, MD, at the 2017 Lynn Sage Breast Cancer Symposium.

About 1 in 5 of the 250,000 new breast cancers diagnosed every year is HER2 positive. The disease used to carry a far worse diagnosis, and has gone from "worst to first" because of the success of the monoclonal antibody drug trastuzumab (Herceptin) in combination with chemotherapy, said Burstein. Disease-free survival rates have increased dramatically since trastuzumab was introduced in 1998, and without significant toxicity from the drug.

In general, about half of diagnoses are stage I. 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, of the Dana-Farber Cancer Institute, said at the symposium, which was sponsored by Northwestern University's Robert H. Lurie Comprehensive Cancer Center.

Patients with more advanced disease may get additional benefits from the use of 2 recently agents: pertuzumab (Perjeta) and neratinib (Nerlynx). Pertuzumab was approved for patients with HER2-positive metastatic breast cancer in 2012 and for neoadjuvant breast cancer treatment in 2013. Neratinib was recently indicated as an adjuvant treatment of early stage HER2-positive breast cancer following 1 year of trastuzumab 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 and chemotherapy for stage II or III disease, and adding adjuvant neratinib at the beginning of year 2 for ER-positive, HER2-positive tumors following one year of trastuzumab. 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 With the approval, the FDA recommended antidiarrheal prophylaxis with the first neratinib dose and continued for 56 days.

Regardless of the newer agents added, trastuzumab remains the starting point, Burstein said. 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.³ A 2-year course did not improve disease-free survival and was associated with more side effects. However, the PHARE trial,⁴ published 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.

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.

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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.